
Mechanisms of cisplatin sensitivity and resistance in testicular germ cell tumors and potential therapeutic agents (Review)
- Authors:
- Ziqing Zhan
- Xia Luo
- Jiaxin Shi
- Litao Chen
- Meng Ye
- Xiaofeng Jin
-
Affiliations: Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, P.R. China - Published online on: February 24, 2025 https://doi.org/10.3892/etm.2025.12832
- Article Number: 82
-
Copyright: © Zhan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
This article is mentioned in:
Abstract
![]() |
![]() |
![]() |
Gilligan T, Lin DW, Aggarwal R, Chism D, Cost N, Derweesh IH, Emamekhoo H, Feldman DR, Geynisman DM, Hancock SL, et al: Testicular cancer, version 2.2020, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 17:1529–1554. 2019.PubMed/NCBI View Article : Google Scholar | |
Winter C and Albers P: Testicular germ cell tumors: Pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 7:43–53. 2011.PubMed/NCBI View Article : Google Scholar | |
Caggiano C, Cavallo F, Giannattasio T, Cappelletti G, Rossi P, Grimaldi P, Feldman DR, Jasin M and Barchi M: Testicular germ cell tumors acquire cisplatin resistance by rebalancing the usage of DNA repair pathways. Cancers (Basel). 13(787)2021.PubMed/NCBI View Article : Google Scholar | |
Shen H, Shih J, Hollern DP, Wang L, Bowlby R, Tickoo SK, Thorsson V, Mungall AJ, Newton Y, Hegde AM, et al: Integrated molecular characterization of testicular germ cell tumors. Cell Rep. 23:3392–3406. 2018.PubMed/NCBI View Article : Google Scholar | |
Batool A, Liu XM, Zhang CL, Hao CF, Chen SR and Liu YX: Recent advances in the regulation of testicular germ cell tumors by microRNAs. Front Biosci (Landmark Ed). 24:765–776. 2019.PubMed/NCBI View Article : Google Scholar | |
Batool A, Karimi N, Wu XN, Chen SR and Liu YX: Testicular germ cell tumor: A comprehensive review. Cell Mol Life Sci. 76:1713–1727. 2019.PubMed/NCBI View Article : Google Scholar | |
Fukawa T and Kanayama HO: Current knowledge of risk factors for testicular germ cell tumors. Int J Urol. 25:337–344. 2018.PubMed/NCBI View Article : Google Scholar | |
Voutsadakis IA: The chemosensitivity of testicular germ cell tumors. Cell Oncol (Dordr). 37:79–94. 2014.PubMed/NCBI View Article : Google Scholar | |
Brown A, Kumar S and Tchounwou PB: Cisplatin-based chemotherapy of human cancers. J Cancer Sci Ther. 11(97)2019.PubMed/NCBI | |
de Vries G, Rosas-Plaza X, van Vugt MATM, Gietema JA and de Jong S: Testicular cancer: Determinants of cisplatin sensitivity and novel therapeutic opportunities. Cancer Treat Rev. 88(102054)2020.PubMed/NCBI View Article : Google Scholar | |
Yang Y, Yang C, Li T, Yu S, Gan T, Hu J, Cui J and Zheng X: The deubiquitinase USP38 promotes NHEJ repair through regulation of HDAC1 activity and regulates cancer cell response to genotoxic insults. Cancer Res. 80:719–731. 2020.PubMed/NCBI View Article : Google Scholar | |
Hoeijmakers JH: DNA damage, aging, and cancer. N Engl J Med. 361:1475–1485. 2009.PubMed/NCBI View Article : Google Scholar | |
Groelly FJ, Fawkes M, Dagg RA, Blackford AN and Tarsounas M: Targeting DNA damage response pathways in cancer. Nat Rev Cancer. 23:78–94. 2023.PubMed/NCBI View Article : Google Scholar | |
Jackson SP and Bartek J: The DNA-damage response in human biology and disease. Nature. 461:1071–1078. 2009.PubMed/NCBI View Article : Google Scholar | |
Yang D and Wang AH: Structural studies of interactions between anticancer platinum drugs and DNA. Prog Biophys Mol Biol. 66:81–111. 1996.PubMed/NCBI View Article : Google Scholar | |
Eastman A: Characterization of the adducts produced in DNA by cis-diamminedichloroplatinum(II) and cis-dichloro(ethylenediamine)platinum(II). Biochemistry. 22:3927–3933. 1983.PubMed/NCBI View Article : Google Scholar | |
Jordan P and Carmo-Fonseca M: Molecular mechanisms involved in cisplatin cytotoxicity. Cell Mol Life Sci. 57:1229–1235. 2000.PubMed/NCBI View Article : Google Scholar | |
Országhová Z, Kalavska K, Mego M and Chovanec M: Overcoming chemotherapy resistance in germ cell tumors. Biomedicines. 10(972)2022.PubMed/NCBI View Article : Google Scholar | |
Welsh C, Day R, McGurk C, Masters JR, Wood RD and Köberle B: Reduced levels of XPA, ERCC1 and XPF DNA repair proteins in testis tumor cell lines. Int J Cancer. 110:352–361. 2004.PubMed/NCBI View Article : Google Scholar | |
Usanova S, Piée-Staffa A, Sied U, Thomale J, Schneider A, Kaina B and Köberle B: Cisplatin sensitivity of testis tumour cells is due to deficiency in interstrand-crosslink repair and low ERCC1-XPF expression. Mol Cancer. 9(248)2010.PubMed/NCBI View Article : Google Scholar | |
Mego M, Cierna Z, Svetlovska D, Macak D, Machalekova K, Miskovska V, Chovanec M, Usakova V, Obertova J, Babal P and Mardiak J: PARP expression in germ cell tumours. J Clin Pathol. 66:607–612. 2013.PubMed/NCBI View Article : Google Scholar | |
Cavallo F, Graziani G, Antinozzi C, Feldman DR, Houldsworth J, Bosl GJ, Chaganti RS, Moynahan ME, Jasin M and Barchi M: Reduced proficiency in homologous recombination underlies the high sensitivity of embryonal carcinoma testicular germ cell tumors to cisplatin and poly (adp-ribose) polymerase inhibition. PLoS One. 7(e51563)2012.PubMed/NCBI View Article : Google Scholar | |
Gutekunst M, Mueller T, Weilbacher A, Dengler MA, Bedke J, Kruck S, Oren M, Aulitzky WE and van der Kuip H: Cisplatin hypersensitivity of testicular germ cell tumors is determined by high constitutive Noxa levels mediated by Oct-4. Cancer Res. 73:1460–1469. 2013.PubMed/NCBI View Article : Google Scholar | |
Koster R, Timmer-Bosscha H, Bischoff R, Gietema JA and de Jong S: Disruption of the MDM2-p53 interaction strongly potentiates p53-dependent apoptosis in cisplatin-resistant human testicular carcinoma cells via the Fas/FasL pathway. Cell Death Dis. 2(e148)2011.PubMed/NCBI View Article : Google Scholar | |
Spierings DCJ, de Vries EGE, Vellenga E and de Jong S: Loss of drug-induced activation of the CD95 apoptotic pathway in a cisplatin-resistant testicular germ cell tumor cell line. Cell Death Differ. 10:808–822. 2003.PubMed/NCBI View Article : Google Scholar | |
Gutekunst M, Oren M, Weilbacher A, Dengler MA, Markwardt C, Thomale J, Aulitzky WE and van der Kuip H: p53 hypersensitivity is the predominant mechanism of the unique responsiveness of testicular germ cell tumor (TGCT) cells to cisplatin. PLoS One. 6(e19198)2011.PubMed/NCBI View Article : Google Scholar | |
Morsi RZ, Hage-Sleiman R, Kobeissy H and Dbaibo G: Noxa: Role in cancer pathogenesis and treatment. Curr Cancer Drug Targets. 18:914–928. 2018.PubMed/NCBI View Article : Google Scholar | |
Schmidtova S, Kalavska K and Kucerova L: Molecular mechanisms of cisplatin chemoresistance and its circumventing in testicular germ cell tumors. Curr Oncol Rep. 20(88)2018.PubMed/NCBI View Article : Google Scholar | |
Woldu SL, Amatruda JF and Bagrodia A: Testicular germ cell tumor genomics. Curr Opin Urol. 27:41–47. 2017.PubMed/NCBI View Article : Google Scholar | |
Lobo J, Alzamora MA, Guimarães R, Cantante M, Lopes P, Braga I, Maurício J, Jerónimo C and Henrique R: p53 and MDM2 expression in primary and metastatic testicular germ cell tumors: Association with clinical outcome. Andrology. 8:1233–1242. 2020.PubMed/NCBI View Article : Google Scholar | |
Han MH, Park SW, Do HJ, Chung HJ, Song H and Kim JH, Kim NH, Park KH and Kim JH: Growth and differentiation factor 3 is transcriptionally regulated by OCT4 in human embryonic carcinoma cells. Biol Pharm Bull. 39:1802–1808. 2016.PubMed/NCBI View Article : Google Scholar | |
Cheng CJ, Wu YC, Shu JA, Ling TY, Kuo HC, Wu JY, Chang EE, Chang SC and Huang YH: Aberrant expression and distribution of the OCT-4 transcription factor in seminomas. J Biomed Sci. 14:797–807. 2007.PubMed/NCBI View Article : Google Scholar | |
Mohiuddin IS, Wei SJ and Kang MH: Role of OCT4 in cancer stem-like cells and chemotherapy resistance. Biochim Biophys Acta Mol Basis Dis. 1866(165432)2020.PubMed/NCBI View Article : Google Scholar | |
Wu YC, Ling TY, Lu SH, Kuo HC, Ho HN, Yeh SD, Shen CN and Huang YH: Chemotherapeutic sensitivity of testicular germ cell tumors under hypoxic conditions is negatively regulated by SENP1-controlled sumoylation of OCT4. Cancer Res. 72:4963–4973. 2012.PubMed/NCBI View Article : Google Scholar | |
Li L, Xu M, Li X, Lv C, Zhang X, Yu H, Zhang M, Fu Y, Meng H and Zhou J: Platelet-derived growth factor-B (PDGF-B) induced by hypoxia promotes the survival of pulmonary arterial endothelial cells through the PI3K/Akt/Stat3 pathway. Cell Physiol Biochem. 35:441–451. 2015.PubMed/NCBI View Article : Google Scholar | |
Pullamsetti SS, Berghausen EM, Dabral S, Tretyn A, Butrous E, Savai R, Butrous G, Dahal BK, Brandes RP, Ghofrani HA, et al: Role of Src tyrosine kinases in experimental pulmonary hypertension. Arterioscler Thromb Vasc Biol. 32:1354–1365. 2012.PubMed/NCBI View Article : Google Scholar | |
Noskovičová N, Petřek M, Eickelberg O and Heinzelmann K: Platelet-derived growth factor signaling in the lung. From lung development and disease to clinical studies. Am J Respir Cell Mol Biol. 52:263–284. 2015.PubMed/NCBI View Article : Google Scholar | |
Rieg AD, Suleiman S, Anker C, Verjans E, Rossaint R, Uhlig S and Martin C: PDGF-BB regulates the pulmonary vascular tone: Impact of prostaglandins, calcium, MAPK- and PI3K/AKT/mTOR signalling and actin polymerisation in pulmonary veins of guinea pigs. Respir Res. 19(120)2018.PubMed/NCBI View Article : Google Scholar | |
Liu P, Cheng H, Roberts TM and Zhao JJ: Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 8:627–644. 2009.PubMed/NCBI View Article : Google Scholar | |
Zhao L and Vogt PK: Class I PI3K in oncogenic cellular transformation. Oncogene. 27:5486–5496. 2008.PubMed/NCBI View Article : Google Scholar | |
Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC and Abraham RT: The PI3K pathway in human disease. Cell. 170:605–635. 2017.PubMed/NCBI View Article : Google Scholar | |
Papa A and Pandolfi PP: The PTEN-PI3K axis in cancer. Biomolecules. 9(153)2019.PubMed/NCBI View Article : Google Scholar | |
Di Vizio D, Cito L, Boccia A, Chieffi P, Insabato L, Pettinato G, Motti ML, Schepis F, D'Amico W, Fabiani F, et al: Loss of the tumor suppressor gene PTEN marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive germ cell tumors. Oncogene. 24:1882–1894. 2005.PubMed/NCBI View Article : Google Scholar | |
Juliachs M, Muñoz C, Moutinho CA, Vidal A, Condom E, Esteller M, Graupera M, Casanovas O, Germà JR, Villanueva A and Viñals F: The PDGFRβ-AKT pathway contributes to CDDP-acquired resistance in testicular germ cell tumors. Clin Cancer Res. 20:658–667. 2014.PubMed/NCBI View Article : Google Scholar | |
Koster R, di Pietro A, Timmer-Bosscha H, Gibcus JH, van den Berg A, Suurmeijer AJ, Bischoff R, Gietema JA and de Jong S: Cytoplasmic p21 expression levels determine cisplatin resistance in human testicular cancer. J Clin Invest. 120:3594–3605. 2010.PubMed/NCBI View Article : Google Scholar | |
Zhang X, Tang N, Hadden TJ and Rishi AK: Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta. 1813:1978–1986. 2011.PubMed/NCBI View Article : Google Scholar | |
Selfe J, Goddard NC, McIntyre A, Taylor KR, Renshaw J, Popov SD, Thway K, Summersgill B, Huddart RA, Gilbert DC and Shipley JM: IGF1R signalling in testicular germ cell tumour cells impacts on cell survival and acquired cisplatin resistance. J Pathol. 244:242–253. 2018.PubMed/NCBI View Article : Google Scholar | |
Gilbert D, Rapley E and Shipley J: Testicular germ cell tumours: Predisposition genes and the male germ cell niche. Nat Rev Cancer. 11:278–288. 2011.PubMed/NCBI View Article : Google Scholar | |
Selfe J and Shipley JM: IGF signalling in germ cells and testicular germ cell tumours: Roles and therapeutic approaches. Andrology. 7:536–544. 2019.PubMed/NCBI View Article : Google Scholar | |
Schneeweiss-Gleixner M, Byrgazov K, Stefanzl G, Berger D, Eisenwort G, Lucini CB, Herndlhofer S, Preuner S, Obrova K, Pusic P, et al: CDK4/CDK6 inhibition as a novel strategy to suppress the growth and survival of BCR-ABL1T315I+ clones in TKI-resistant CML. EBioMedicine. 50:111–121. 2019.PubMed/NCBI View Article : Google Scholar | |
Rossini E, Bosatta V, Abate A, Fragni M, Salvi V, Basnet RM, Zizioli D, Bosisio D, Piovani G, Valcamonico F, et al: Cisplatin cytotoxicity in human testicular germ cell tumor cell lines is enhanced by the CDK4/6 inhibitor palbociclib. Clin Genitourin Cancer. 19:316–324. 2021.PubMed/NCBI View Article : Google Scholar | |
Mayer F, Stoop H, Scheffer GL, Scheper R, Oosterhuis JW, Looijenga LH and Bokemeyer C: Molecular determinants of treatment response in human germ cell tumors. Clin Cancer Res. 9:767–773. 2003.PubMed/NCBI | |
Jacobsen C and Honecker F: Cisplatin resistance in germ cell tumours: Models and mechanisms. Andrology. 3:111–121. 2015.PubMed/NCBI View Article : Google Scholar | |
Oosterhuis JW and Looijenga LHJ: Human germ cell tumours from a developmental perspective. Nat Rev Cancer. 19:522–537. 2019.PubMed/NCBI View Article : Google Scholar | |
Sonnenburg D, Spinella MJ and Albany C: Epigenetic targeting of platinum resistant testicular cancer. Curr Cancer Drug Targets. 16:789–795. 2016.PubMed/NCBI View Article : Google Scholar | |
Fazal Z, Singh R, Fang F, Bikorimana E, Baldwin H, Corbet A, Tomlin M, Yerby C, Adra N, Albany C, et al: Hypermethylation and global remodelling of DNA methylation is associated with acquired cisplatin resistance in testicular germ cell tumours. Epigenetics. 16:1071–1084. 2021.PubMed/NCBI View Article : Google Scholar | |
Liu ZX, Li LM, Sun HL and Liu SM: Link between m6A modification and cancers. Front Bioeng Biotechnol. 6(89)2018.PubMed/NCBI View Article : Google Scholar | |
Miranda-Gonçalves V, Lobo J, Guimarães-Teixeira C, Barros-Silva D, Guimarães R, Cantante M, Braga I, Maurício J, Oing C, Honecker F, et al: The component of the m6A writer complex VIRMA is implicated in aggressive tumor phenotype, DNA damage response and cisplatin resistance in germ cell tumors. J Exp Clin Cancer Res. 40(268)2021.PubMed/NCBI View Article : Google Scholar | |
Wei J, Yin Y, Zhou J, Chen H, Peng J, Yang J and Tang Y: METTL3 potentiates resistance to cisplatin through m6A modification of TFAP2C in seminoma. J Cell Mol Med. 24:11366–11380. 2020.PubMed/NCBI View Article : Google Scholar | |
Doghish AS, Moustafa HAM, Elballal MS, Sallam AM, El-Dakroury WA, Abdel Mageed SS, Elesawy AE, Abdelmaksoud NM, Shahin RK, Midan HM, et al: The potential role of miRNAs in the pathogenesis of testicular germ cell tumors-A Focus on signaling pathways interplay. Pathol Res Pract. 248(154611)2023.PubMed/NCBI View Article : Google Scholar | |
Sawant A, Floyd AM, Dangeti M, Lei W, Sobol RW and Patrick SM: Differential role of base excision repair proteins in mediating cisplatin cytotoxicity. DNA Repair (Amst). 51:46–59. 2017.PubMed/NCBI View Article : Google Scholar | |
Cavallo F, Caggiano C, Jasin M and Barchi M: Assessing homologous recombination and interstrand cross-link repair in embryonal carcinoma testicular germ cell tumor cell lines. Methods Mol Biol. 2195:113–123. 2021.PubMed/NCBI View Article : Google Scholar | |
Pannunzio NR, Watanabe G and Lieber MR: Nonhomologous DNA end-joining for repair of DNA double-strand breaks. J Biol Chem. 293:10512–10523. 2018.PubMed/NCBI View Article : Google Scholar | |
Scully R, Panday A, Elango R and Willis NA: DNA double-strand break repair-pathway choice in somatic mammalian cells. Nat Rev Mol Cell Biol. 20:698–714. 2019.PubMed/NCBI View Article : Google Scholar | |
Chang HHY, Pannunzio NR, Adachi N and Lieber MR: Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat Rev Mol Cell Biol. 18:495–506. 2017.PubMed/NCBI View Article : Google Scholar | |
Sugitani N, Sivley RM, Perry KE, Capra JA and Chazin WJ: XPA: A key scaffold for human nucleotide excision repair. DNA Repair (Amst). 44:123–135. 2016.PubMed/NCBI View Article : Google Scholar | |
Cierna Z, Miskovska V, Roska J, Jurkovicova D, Pulzova LB, Sestakova Z, Hurbanova L, Machalekova K, Chovanec M, Rejlekova K, et al: Increased levels of XPA might be the basis of cisplatin resistance in germ cell tumours. BMC Cancer. 20(17)2020.PubMed/NCBI View Article : Google Scholar | |
Clairmont CS and D'Andrea AD: REV7 directs DNA repair pathway choice. Trends Cell Biol. 31:965–978. 2021.PubMed/NCBI View Article : Google Scholar | |
Dash RC and Hadden K: Protein-protein interactions in translesion synthesis. Molecules. 26(5544)2021.PubMed/NCBI View Article : Google Scholar | |
Shimada Y, Kato T, Sakurai Y, Watanabe H, Nonaka M, Nanaura N, Ichinoe M and Murakumo Y: Identification of the promoter region regulating the transcription of the REV7 gene. Biochem Biophys Res Commun. 662:8–17. 2023.PubMed/NCBI View Article : Google Scholar | |
Sakurai Y, Ichinoe M, Yoshida K, Nakazato Y, Saito S, Satoh M, Nakada N, Sanoyama I, Umezawa A, Numata Y, et al: Inactivation of REV7 enhances chemosensitivity and overcomes acquired chemoresistance in testicular germ cell tumors. Cancer Lett. 489:100–110. 2020.PubMed/NCBI View Article : Google Scholar | |
Funke K, Einsfelder U, Hansen A, Arévalo L, Schneider S, Nettersheim D, Stein V and Schorle H: Genome-scale CRISPR screen reveals neddylation to contribute to cisplatin resistance of testicular germ cell tumours. Br J Cancer. 128:2270–2282. 2023.PubMed/NCBI View Article : Google Scholar | |
Hinz S, Magheli A, Weikert S, Schulze W, Krause H, Schrader M, Miller K and Kempkensteffen C: Deregulation of EZH2 expression in human spermatogenic disorders and testicular germ cell tumors. World J Urol. 28:631–635. 2010.PubMed/NCBI View Article : Google Scholar | |
Yamagishi M and Uchimaru K: Targeting EZH2 in cancer therapy. Curr Opin Oncol. 29:375–381. 2017.PubMed/NCBI View Article : Google Scholar | |
Sun S, Zhao S, Yang Q, Wang W, Cai E, Wen Y, Yu L, Wang Z and Cai J: Enhancer of zeste homolog 2 promotes cisplatin resistance by reducing cellular platinum accumulation. Cancer Sci. 109:1853–1864. 2018.PubMed/NCBI View Article : Google Scholar | |
Dou D, Ge X, Wang X, Xu X, Zhang Z, Seng J, Cao Z, Gu Y and Han M: EZH2 contributes to cisplatin resistance in breast cancer by epigenetically suppressing miR-381 expression. Onco Targets Ther. 12:9627–9637. 2019.PubMed/NCBI View Article : Google Scholar | |
Xu C, Hao K, Hu H, Sheng Z, Yan J, Wang Q and Yu L: Expression of the enhancer of zeste homolog 2 in biopsy specimen predicts chemoresistance and survival in advanced non-small cell lung cancer receiving first-line platinum-based chemotherapy. Lung Cancer. 86:268–273. 2014.PubMed/NCBI View Article : Google Scholar | |
Singh R, Fazal Z, Corbet AK, Bikorimana E, Rodriguez JC, Khan EM, Shahid K, Freemantle SJ and Spinella MJ: Epigenetic remodeling through downregulation of polycomb repressive complex 2 mediates chemotherapy resistance in testicular germ cell tumors. Cancers (Basel). 11(796)2019.PubMed/NCBI View Article : Google Scholar | |
Samaržija I, Tomljanović M, Novak Kujundžić R and Trošelj KG: EZH2 inhibition and cisplatin as a combination anticancer therapy: An overview of preclinical studies. Cancers (Basel). 14(4761)2022.PubMed/NCBI View Article : Google Scholar | |
Singh R, Fazal Z, Bikorimana E, Boyd RI, Yerby C, Tomlin M, Baldwin H, Shokry D, Corbet AK, Shahid K, et al: Reciprocal epigenetic remodeling controls testicular cancer hypersensitivity to hypomethylating agents and chemotherapy. Mol Oncol. 16:683–698. 2022.PubMed/NCBI View Article : Google Scholar | |
Timmerman DM, Eleveld TF, Sriram S, Dorssers LCJ, Gillis AJM, Schmidtova S, Kalavska K, van de Werken HJG, Oing C, Honecker F, et al: Chromosome 3p25.3 gain is associated with cisplatin resistance and is an independent predictor of poor outcome in male malignant germ cell tumors. J Clin Oncol. 40:3077–3087. 2022.PubMed/NCBI View Article : Google Scholar | |
Yu H: Structural activation of Mad2 in the mitotic spindle checkpoint: The two-state Mad2 model versus the Mad2 template model. J Cell Biol. 173:153–157. 2006.PubMed/NCBI View Article : Google Scholar | |
Henriques AC, Silva PMA, Sarmento B and Bousbaa H: The Mad2-binding protein p31comet as a potential target for human cancer therapy. Curr Cancer Drug Targets. 21:401–415. 2021.PubMed/NCBI View Article : Google Scholar | |
López-Saavedra A, Ramírez-Otero M, Díaz-Chávez J, Cáceres-Gutiérrez R, Justo-Garrido M, Andonegui MA, Mendoza J, Downie-Ruíz Á, Cortés-González C, Reynoso N, et al: MAD2γ, a novel MAD2 isoform, reduces mitotic arrest and is associated with resistance in testicular germ cell tumors. Cell Cycle. 15:2066–2076. 2016.PubMed/NCBI View Article : Google Scholar | |
Kitayama S, Ikeda K, Sato W, Takeshita H, Kawakami S, Inoue S and Horie K: Testis-expressed gene 11 inhibits cisplatin-induced DNA damage and contributes to chemoresistance in testicular germ cell tumor. Sci Rep. 12(18423)2022.PubMed/NCBI View Article : Google Scholar | |
McHugh DJ, Gleeson JP and Feldman DR: Testicular cancer in 2023: Current status and recent progress. CA Cancer J Clin. 74:167–186. 2024.PubMed/NCBI View Article : Google Scholar | |
Paffenholz P, Pfister D and Heidenreich A: Testis-preserving strategies in testicular germ cell tumors and germ cell neoplasia in situ. Transl Androl Urol. 9 (Suppl 1):S24–S30. 2020.PubMed/NCBI View Article : Google Scholar | |
Chang MM, Pan BS, Wang CY and Huang BM: Cordycepin-induced unfolded protein response-dependent cell death, and AKT/MAPK-mediated drug resistance in mouse testicular tumor cells. Cancer Med. 8:3949–3964. 2019.PubMed/NCBI View Article : Google Scholar | |
Hu Z, Yu J, Gui G, Chen Y, Huang R, Jiang L, Kwong JSW, Li Y and Zhang L: Cisplatin for testicular germ cell tumors: A rapid review. J Evid Based Med. 9:144–151. 2016.PubMed/NCBI View Article : Google Scholar | |
Chovanec M, Hanna N, Cary KC, Einhorn L and Albany C: Management of stage I testicular germ cell tumours. Nat Rev Urol. 13:663–673. 2016.PubMed/NCBI View Article : Google Scholar | |
Sadek KM, AbdEllatief HY, Mahmoud SFE, Alexiou A, Papadakis M, Al-Hajeili M, Saad HM and Batiha GE: New insights on testicular cancer prevalence with novel diagnostic biomarkers and therapeutic approaches. Cancer Rep (Hoboken). 7(e2052)2024.PubMed/NCBI View Article : Google Scholar | |
Curreri SA, Fung C and Beard CJ: Secondary malignant neoplasms in testicular cancer survivors. Urol Oncol. 33:392–398. 2015.PubMed/NCBI View Article : Google Scholar | |
Beitzen-Heineke A, Rolling CC, Seidel C, Erley J, Molwitz I, Muellerleile K, Saering D, Senftinger J, Börschel N, Engel NW, et al: Long-term cardiotoxicity in germ cell cancer survivors after platinum-based chemotherapy: Cardiac MR shows impaired systolic function and tissue alterations. Eur Radiol. 34:4102–4112. 2024.PubMed/NCBI View Article : Google Scholar | |
Chovanec M, Abu Zaid M, Hanna N, El-Kouri N, Einhorn LH and Albany C: Long-term toxicity of cisplatin in germ-cell tumor survivors. Ann Oncol. 28:2670–2679. 2017.PubMed/NCBI View Article : Google Scholar | |
Porcu P, Bhatia S, Sharma M and Einhorn LH: Results of treatment after relapse from high-dose chemotherapy in germ cell tumors. J Clin Oncol. 18:1181–1186. 2000.PubMed/NCBI View Article : Google Scholar | |
Chieffi P, De Martino M and Esposito F: Further insights into testicular germ cell tumor oncogenesis: Potential therapeutic targets. Expert Rev Anticancer Ther. 20:189–195. 2020.PubMed/NCBI View Article : Google Scholar | |
Einhorn LH, Williams SD, Chamness A, Brames MJ, Perkins SM and Abonour R: High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med. 357:340–348. 2007.PubMed/NCBI View Article : Google Scholar | |
Lorch A, Bascoul-Mollevi C, Kramar A, Einhorn L, Necchi A, Massard C, De Giorgi U, Fléchon A, Margolin K, Lotz JP, et al: Conventional-dose versus high-dose chemotherapy as first salvage treatment in male patients with metastatic germ cell tumors: Evidence from a large international database. J Clin Oncol. 29:2178–2184. 2011.PubMed/NCBI View Article : Google Scholar | |
Nichols CR, Tricot G, Williams SD, van Besien K, Loehrer PJ, Roth BJ, Akard L, Hoffman R, Goulet R, Wolff SN, et al: Dose-intensive chemotherapy in refractory germ cell cancer-a phase I/II trial of high-dose carboplatin and etoposide with autologous bone marrow transplantation. J Clin Oncol. 7:932–939. 1989.PubMed/NCBI View Article : Google Scholar | |
Su X, Wang Z, Li L, Zheng M, Zheng C, Gong P, Zhao P, Ma Y, Tao Q and Cai L: Lipid-polymer nanoparticles encapsulating doxorubicin and 2'-deoxy-5-azacytidine enhance the sensitivity of cancer cells to chemical therapeutics. Mol Pharm. 10:1901–1909. 2013.PubMed/NCBI View Article : Google Scholar | |
Ohtani H, Ørskov AD, Helbo AS, Gillberg L, Liu M, Zhou W, Ungerstedt J, Hellström-Lindberg E, Sun W, Liang G, et al: Activation of a subset of evolutionarily young transposable elements and innate immunity are linked to clinical responses to 5-azacytidine. Cancer Res. 80:2441–2450. 2020.PubMed/NCBI View Article : Google Scholar | |
Stahl M, Kohrman N, Gore SD, Kim TK, Zeidan AM and Prebet T: Epigenetics in cancer: A hematological perspective. PLoS Genet. 12(e1006193)2016.PubMed/NCBI View Article : Google Scholar | |
Lobo J, Guimarães-Teixeira C, Barros-Silva D, Miranda-Gonçalves V, Camilo V, Guimarães R, Cantante M, Braga I, Maurício J, Oing C, et al: Efficacy of HDAC inhibitors belinostat and panobinostat against cisplatin-sensitive and cisplatin-resistant testicular germ cell tumors. Cancers (Basel). 12(2903)2020.PubMed/NCBI View Article : Google Scholar | |
Cardoso AR, Lobo J, Miranda-Gonçalves V, Henrique R and Jerónimo C: Epigenetic alterations as therapeutic targets in testicular germ cell tumours: Current and future application of ‘epidrugs’. Epigenetics. 16:353–372. 2021.PubMed/NCBI View Article : Google Scholar | |
Lobo J, Cardoso AR, Miranda-Gonçalves V, Looijenga LHJ, Lopez M, Arimondo PB, Henrique R and Jerónimo C: Targeting germ cell tumors with the newly synthesized flavanone-derived compound MLo1302 efficiently reduces tumor cell viability and induces apoptosis and cell cycle arrest. Pharmaceutics. 13(73)2021.PubMed/NCBI View Article : Google Scholar | |
Albany C, Hever-Jardine MP, von Herrmann KM, Yim CY, Tam J, Warzecha JM, Shin L, Bock SE, Curran BS, Chaudhry AS, et al: Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methylation inhibitor guadecitabine. Oncotarget. 8:2949–2959. 2017.PubMed/NCBI View Article : Google Scholar | |
Oing C, Verem I, Mansour WY, Bokemeyer C, Dyshlovoy S and Honecker F: 5-Azacitidine exerts prolonged pro-apoptotic effects and overcomes cisplatin-resistance in non-seminomatous germ cell tumor cells. Int J Mol Sci. 20(21)2018.PubMed/NCBI View Article : Google Scholar | |
Jostes S, Nettersheim D, Fellermeyer M, Schneider S, Hafezi F, Honecker F, Schumacher V, Geyer M, Kristiansen G and Schorle H: The bromodomain inhibitor JQ1 triggers growth arrest and apoptosis in testicular germ cell tumours in vitro and in vivo. J Cell Mol Med. 21:1300–1314. 2017.PubMed/NCBI View Article : Google Scholar | |
Zhou W, Chen H, Hong X, Niu X and Lu Q: Knockdown of DNA methyltransferase-1 inhibits proliferation and derepresses tumor suppressor genes in myeloma cells. Oncol Lett. 8:2130–2134. 2014.PubMed/NCBI View Article : Google Scholar | |
Tulsyan S, Aftab M, Sisodiya S, Khan A, Chikara A, Tanwar P and Hussain S: Molecular basis of epigenetic regulation in cancer diagnosis and treatment. Front Genet. 13(885635)2022.PubMed/NCBI View Article : Google Scholar | |
Lecomte S, Demay F, Ferrière F and Pakdel F: Phytochemicals targeting estrogen receptors: Beneficial rather than adverse effects? Int J Mol Sci. 18(1381)2017.PubMed/NCBI View Article : Google Scholar | |
Van Neste L, Bigley J, Toll A, Otto G, Clark J, Delrée P, Van Criekinge W and Epstein JI: A tissue biopsy-based epigenetic multiplex PCR assay for prostate cancer detection. BMC Urol. 12(16)2012.PubMed/NCBI View Article : Google Scholar | |
Jin B and Robertson KD: DNA methyltransferases, DNA damage repair, and cancer. Adv Exp Med Biol. 754:3–29. 2013.PubMed/NCBI View Article : Google Scholar | |
Stresemann C and Lyko F: Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 123:8–13. 2008.PubMed/NCBI View Article : Google Scholar | |
Hollenbach PW, Nguyen AN, Brady H, Williams M, Ning Y, Richard N, Krushel L, Aukerman SL, Heise C and MacBeth KJ: A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One. 5(e9001)2010.PubMed/NCBI View Article : Google Scholar | |
Wermann H, Stoop H, Gillis AJM, Honecker F, van Gurp RJ, Ammerpohl O, Richter J, Oosterhuis JW, Bokemeyer C and Looijenga LH: Global DNA methylation in fetal human germ cells and germ cell tumours: Association with differentiation and cisplatin resistance. J Pathol. 221:433–442. 2010.PubMed/NCBI View Article : Google Scholar | |
Rüter B, Wijermans PW and Lübbert M: DNA methylation as a therapeutic target in hematologic disorders: Recent results in older patients with myelodysplasia and acute myeloid leukemia. Int J Hematol. 80:128–135. 2004.PubMed/NCBI View Article : Google Scholar | |
Beyrouthy MJ, Garner KM, Hever MP, Freemantle SJ, Eastman A, Dmitrovsky E and Spinella MJ: High DNA methyltransferase 3B expression mediates 5-aza-deoxycytidine hypersensitivity in testicular germ cell tumors. Cancer Res. 69:9360–9366. 2009.PubMed/NCBI View Article : Google Scholar | |
Issa JJ, Roboz G, Rizzieri D, Jabbour E, Stock W, O'Connell C, Yee K, Tibes R, Griffiths EA, Walsh K, et al: Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: A multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol. 16:1099–1110. 2015.PubMed/NCBI View Article : Google Scholar | |
Albany C, Fazal Z, Singh R, Bikorimana E, Adra N, Hanna NH, Einhorn LH, Perkins SM, Sandusky GE, Christensen BC, et al: A phase 1 study of combined guadecitabine and cisplatin in platinum refractory germ cell cancer. Cancer Med. 10:156–163. 2021.PubMed/NCBI View Article : Google Scholar | |
Kurz L, Miklyaeva A, Skowron MA, Overbeck N, Poschmann G, Becker T, Eul K, Kurz T, Schönberger S, Calaminus G, et al: ARID1A regulates transcription and the epigenetic landscape via POLE and DMAP1 while ARID1A deficiency or pharmacological inhibition sensitizes germ cell tumor cells to ATR inhibition. Cancers (Basel). 12(905)2020.PubMed/NCBI View Article : Google Scholar | |
Steinemann G, Dittmer A, Kuzyniak W, Hoffmann B, Schrader M, Schobert R, Biersack B, Nitzsche B and Höpfner M: Animacroxam, a novel dual-mode compound targeting histone deacetylases and cytoskeletal integrity of testicular germ cell cancer cells. Mol Cancer Ther. 16:2364–2374. 2017.PubMed/NCBI View Article : Google Scholar | |
Steinemann G, Dittmer A, Schmidt J, Josuttis D, Fähling M, Biersack B, Beindorff N, Jolante Koziolek E, Schobert R, Brenner W, et al: Antitumor and antiangiogenic activity of the novel chimeric inhibitor animacroxam in testicular germ cell cancer. Mol Oncol. 13:2679–2696. 2019.PubMed/NCBI View Article : Google Scholar | |
Nettersheim D, Berger D, Jostes S, Skowron M and Schorle H: Deciphering the molecular effects of romidepsin on germ cell tumours: DHRS2 is involved in cell cycle arrest but not apoptosis or induction of romidepsin effectors. J Cell Mol Med. 23:670–679. 2019.PubMed/NCBI View Article : Google Scholar | |
Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, et al: BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 146:904–917. 2011.PubMed/NCBI View Article : Google Scholar | |
Burmeister A, Stephan A, Alves Avelar LA, Müller MR, Seiwert A, Höfmann S, Fischer F, Torres-Gomez H, Hoffmann MJ, Niegisch G, et al: Establishment and evaluation of dual HDAC/BET inhibitors as therapeutic options for germ cell tumors and other urological malignancies. Mol Cancer Ther. 21:1674–1688. 2022.PubMed/NCBI View Article : Google Scholar | |
Lengert AVH, Pereira LDNB, Cabral ERM, Gomes INF, Jesus LM, Gonçalves MFS, Rocha AOD, Tassinari TA, Silva LSD, Laus AC, et al: Potential new therapeutic approaches for cisplatin-resistant testicular germ cell tumors. Front Biosci (Landmark Ed). 27(245)2022.PubMed/NCBI View Article : Google Scholar | |
Huang TT, Nijman SMB, Mirchandani KD, Galardy PJ, Cohn MA, Haas W, Gygi SP, Ploegh HL, Bernards R and D'Andrea AD: Regulation of monoubiquitinated PCNA by DUB autocleavage. Nat Cell Biol. 8:339–347. 2006.PubMed/NCBI View Article : Google Scholar | |
Hasibeder A, Venkataramani V, Thelen P, Radzun HJ and Schweyer S: Phytoestrogens regulate the proliferation and expression of stem cell factors in cell lines of malignant testicular germ cell tumors. Int J Oncol. 43:1385–1394. 2013.PubMed/NCBI View Article : Google Scholar | |
Kalavska K, Schmidtova S, Chovanec M and Mego M: Immunotherapy in testicular germ cell tumors. Front Oncol. 10(573977)2020.PubMed/NCBI View Article : Google Scholar | |
Vincent AJ, Ren S, Harris LG, Devine DJ, Samant RS, Fodstad O and Shevde LA: Cytoplasmic translocation of p21 mediates NUPR1-induced chemoresistance: NUPR1 and p21 in chemoresistance. FEBS Lett. 586:3429–3434. 2012.PubMed/NCBI View Article : Google Scholar | |
Xia X, Ma Q, Li X, Ji T, Chen P, Xu H, Li K, Fang Y, Weng D, Weng Y, et al: Cytoplasmic p21 is a potential predictor for cisplatin sensitivity in ovarian cancer. BMC Cancer. 11(399)2011.PubMed/NCBI View Article : Google Scholar | |
Wang X, Wang Y, Gou S and Chen F: A trifunctional Pt(II) complex alleviates the NHEJ/HR-related DSBs repairs to evade cisplatin-resistance in NSCLC. Bioorg Chem. 104(104210)2020.PubMed/NCBI View Article : Google Scholar | |
Costa A, Forte IM, Pentimalli F, Iannuzzi CA, Alfano L, Capone F, Camerlingo R, Calabrese A, von Arx C, Benot Dominguez R, et al: Pharmacological inhibition of CDK4/6 impairs diffuse pleural mesothelioma 3D spheroid growth and reduces viability of cisplatin-resistant cells. Front Oncol. 14(1418951)2024.PubMed/NCBI View Article : Google Scholar | |
Romano FJ, Rossetti S, Conteduca V, Schepisi G, Cavaliere C, Di Franco R, La Mantia E, Castaldo L, Nocerino F, Ametrano G, et al: Role of DNA repair machinery and p53 in the testicular germ cell cancer: A review. Oncotarget. 7:85641–85649. 2016.PubMed/NCBI View Article : Google Scholar | |
Spierings DC, de Vries EG, Stel AJ, te Rietstap N, Vellenga E and de Jong S: Low p21Waf1/Cip1 protein level sensitizes testicular germ cell tumor cells to Fas-mediated apoptosis. Oncogene. 23:4862–4872. 2004.PubMed/NCBI View Article : Google Scholar | |
Tomida J, Takata KI, Bhetawal S, Person MD, Chao HP, Tang DG and Wood RD: FAM35A associates with REV7 and modulates DNA damage responses of normal and BRCA1-defective cells. EMBO J. 37(e99543)2018.PubMed/NCBI View Article : Google Scholar | |
Lind GE, Skotheim RI, Fraga MF, Abeler VM, Esteller M and Lothe RA: Novel epigenetically deregulated genes in testicular cancer include homeobox genes and SCGB3A1 (HIN-1). J Pathol. 210:441–449. 2006.PubMed/NCBI View Article : Google Scholar | |
Roška J, Wachsmannová L, Hurbanová L, Šestáková Z, Mueller T, Jurkovičová D and Chovanec M: Differential gene expression in cisplatin-resistant and -sensitive testicular germ cell tumor cell lines. Oncotarget. 11:4735–4753. 2020.PubMed/NCBI View Article : Google Scholar | |
Schmidtova S, Dorssers LCJ, Kalavska K, Gillis AJM, Oosterhuis JW, Stoop H, Miklikova S, Kozovska Z, Burikova M, Gercakova K, et al: Napabucasin overcomes cisplatin resistance in ovarian germ cell tumor-derived cell line by inhibiting cancer stemness. Cancer Cell Int. 20(364)2020.PubMed/NCBI View Article : Google Scholar | |
Schmidtova S, Kalavska K, Gercakova K, Cierna Z, Miklikova S, Smolkova B, Buocikova V, Miskovska V, Durinikova E, Burikova M, et al: Disulfiram overcomes cisplatin resistance in human embryonal carcinoma cells. Cancers (Basel). 11(1224)2019.PubMed/NCBI View Article : Google Scholar | |
Ma H, Cao W and Ding M: MicroRNA-31 weakens cisplatin resistance of medulloblastoma cells via NF-κB and PI3K/AKT pathways. Biofactors. 46:831–838. 2020.PubMed/NCBI View Article : Google Scholar | |
Luo H, Yi T, Huang D, Chen X, Li X, Wan Q, Huang H, Huang H, Wei H, Song Y, et al: circ_PTN contributes to -cisplatin resistance in glioblastoma via PI3K/AKT signaling through the miR-542-3p/PIK3R3 pathway. Mol Ther Nucleic Acids. 26:1255–1269. 2021.PubMed/NCBI View Article : Google Scholar | |
Fankhauser CD, Curioni-Fontecedro A, Allmann V, Beyer J, Tischler V, Sulser T, Moch H and Bode PK: Frequent PD-L1 expression in testicular germ cell tumors. Br J Cancer. 113:411–413. 2015.PubMed/NCBI View Article : Google Scholar | |
Hong W, Xue M, Jiang J, Zhang Y and Gao X: Circular RNA circ-CPA4/let-7 miRNA/PD-L1 axis regulates cell growth, stemness, drug resistance and immune evasion in non-small cell lung cancer (NSCLC). J Exp Clin Cancer Res. 39(149)2020.PubMed/NCBI View Article : Google Scholar | |
De S, Holvey-Bates EG, Mahen K, Willard B and Stark GR: The ubiquitin E3 ligase FBXO22 degrades PD-L1 and sensitizes cancer cells to DNA damage. Proc Natl Acad Sci USA. 118(e2112674118)2021.PubMed/NCBI View Article : Google Scholar | |
Liu L, Lian J, Zhang H, Tian H, Liang M, Yin M and Sun F: MicroRNA-302a sensitizes testicular embryonal carcinoma cells to cisplatin-induced cell death. J Cell Physiol. 228:2294–2304. 2013.PubMed/NCBI View Article : Google Scholar | |
Wei J, Gan Y, Peng D, Jiang X, Kitazawa R, Xiang Y, Dai Y, Tang Y and Yang J: Long non-coding RNA H19 promotes TDRG1 expression and cisplatin resistance by sequestering miRNA-106b-5p in seminoma. Cancer Med. 7:6247–6257. 2018.PubMed/NCBI View Article : Google Scholar | |
Huang H, Tian H, Duan Z, Cao Y, Zhang XS and Sun F: microRNA-383 impairs phosphorylation of H2AX by targeting PNUTS and inducing cell cycle arrest in testicular embryonal carcinoma cells. Cell Signal. 26:903–911. 2014.PubMed/NCBI View Article : Google Scholar | |
Elesawy AE, Abulsoud AI, Moustafa HAM, Elballal MS, Sallam AM, Elazazy O, El-Dakroury WA, Abdel Mageed SS, Abdelmaksoud NM, Midan HM, et al: miRNAs orchestration of testicular germ cell tumors-particular emphasis on diagnosis, progression and drug resistance. Pathol Res Pract. 248(154612)2023.PubMed/NCBI View Article : Google Scholar | |
Özata DM, Li X, Lee L, Liu J, Warsito D, Hajeri P, Hultman I, Fotouhi O, Marklund S, Ährlund-Richter L, et al: Loss of miR-514a-3p regulation of PEG3 activates the NF-kappa B pathway in human testicular germ cell tumors. Cell Death Dis. 8(e2759)2017.PubMed/NCBI View Article : Google Scholar | |
Roška J, Lobo J, Ivovič D, Wachsmannová L, Mueller T, Henrique R, Jerónimo C, Chovanec M and Jurkovičová D: Integrated microarray-based data analysis of miRNA expression profiles: Identification of novel biomarkers of cisplatin-resistance in testicular germ cell tumours. Int J Mol Sci. 24(2495)2023.PubMed/NCBI View Article : Google Scholar |