BMH-21 inhibits viability and induces apoptosis by p53-dependent nucleolar stress responses in SKOV3 ovarian cancer cells

Fu,Xinxu; Xu,Lu; Qi,Ling; Tian,Hongyan; Yi,Dan; Yu,Yang; Liu,Shibing; Li,Songyan; Xu,Ye; Wang,Chunyan

doi:10.3892/or.2017.5750

BMH-21 inhibits viability and induces apoptosis by p53-dependent nucleolar stress responses in SKOV3 ovarian cancer cells

Authors:
- Xinxu Fu
- Lu Xu
- Ling Qi
- Hongyan Tian
- Dan Yi
- Yang Yu
- Shibing Liu
- Songyan Li
- Ye Xu
- Chunyan Wang
View Affiliations

Affiliations: Tumor Targeted Therapy and Translational Medicine Laboratory, Basic College of Medicine, Jilin Medical University, Jilin, Jilin 132013, P.R. China, Department of Histology and Embryology, Basic College of Medicine, Jilin Medical University, Jilin, Jilin 132013, P.R. China, Physical Examination Center, Jilin Integrated Traditional Chinese and Western Medicine Hospital, Jilin, Jilin 132013, P.R. China
Published online on: June 23, 2017 https://doi.org/10.3892/or.2017.5750
Pages: 859-865
Copyright: © Fu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The nucleolus is a stress sensor associated with cell cycle progression and apoptosis. Studies have shown that nucleolar stress is positively correlated with apoptosis in breast, prostate and lung cancer cells. However, the role and function of nucleolar stress in ovarian cancer has not been reported. In this study, we found that the nucleolar stress inducer BMH-21 inhibited viability of SKOV3 ovarian cancer cells in a dose-dependent manner. Furthermore, BMH-21 induced the expression of nucleolar stress marker proteins (nucleolin, nucleophosmin and fibrillarin) and promoted the nuclear export of these proteins. BMH-21 also decreased MDM2 proto-oncogene expression and increased protein levels of the tumor suppressor p53 and p53 phosphorylated at serine 15 (p‑p53‑Ser15), which contributed to increased expression of the downstream apoptosis-related protein BCL2 associated X (BAX) and activation of caspase-3. Taken together, these data provide the first reported evidence that induction of p53-dependent nucleolar stress by BMH-21 induces apoptosis in ovarian cancer. Our data suggest that nucleolar stress might be a pathway suitable for targeting in ovarian cancer.

View Figures

View References

1	Xie S, Zheng H, Wen X, Sun J, Wang Y, Gao X, Guo L and Lu R: MUS81 is associated with cell proliferation and cisplatin sensitivity in serous ovarian cancer. Biochem Biophys Res Commun. 476:493–500. 2016. View Article : Google Scholar : PubMed/NCBI
2	Gershenson DM and Frazier AL: Conundrums in the management of malignant ovarian germ cell tumors: Toward lessening acute morbidity and late effects of treatment. Gynecol Oncol. 143:428–432. 2016. View Article : Google Scholar : PubMed/NCBI
3	Wijdeven RH, Pang B, Assaraf YG and Neefjes J: Old drugs, novel ways out: Drug resistance toward cytotoxic chemotherapeutics. Drug Resist Updat. 28:65–81. 2016. View Article : Google Scholar : PubMed/NCBI
4	Yang L and Chen J: SirT1 and rRNA in the nucleolus: Regulating the regulator. Oncoscience. 1:111–112. 2014. View Article : Google Scholar : PubMed/NCBI
5	Hariharan N and Sussman MA: Stressing on the nucleolus in cardiovascular disease. Biochim Biophys Acta. 1842:798–801. 2014. View Article : Google Scholar : PubMed/NCBI
6	Quin JE, Devlin JR, Cameron D, Hannan KM, Pearson RB and Hannan RD: Targeting the nucleolus for cancer intervention. Biochim Biophys Acta. 1842:802–816. 2014. View Article : Google Scholar : PubMed/NCBI
7	Hein N, Hannan KM, George AJ, Sanij E and Hannan RD: The nucleolus: An emerging target for cancer therapy. Trends Mol Med. 19:643–654. 2013. View Article : Google Scholar : PubMed/NCBI
8	Colis L, Ernst G, Sanders S, Liu H, Sirajuddin P, Peltonen K, DePasquale M, Barrow JC and Laiho M: Design, synthesis, and structure-activity relationships of pyridoquinazolinecarboxamides as RNA polymerase I inhibitors. J Med Chem. 57:4950–4961. 2014. View Article : Google Scholar : PubMed/NCBI
9	Peltonen K, Colis L, Liu H, Jäämaa S, Moore HM, Enbäck J, Laakkonen P, Vaahtokari A, Jones RJ, af Hällström TM, et al: Identification of novel p53 pathway activating small-molecule compounds reveals unexpected similarities with known therapeutic agents. PLoS One. 5:e129962010. View Article : Google Scholar : PubMed/NCBI
10	Peltonen K, Colis L, Liu H, Trivedi R, Moubarek MS, Moore HM, Bai B, Rudek MA, Bieberich CJ and Laiho M: A targeting modality for destruction of RNA polymerase I that possesses anticancer activity. Cancer Cell. 25:77–90. 2014. View Article : Google Scholar : PubMed/NCBI
11	Zhang X and Yu H: Matrine inhibits diethylnitrosamine-induced HCC proliferation in rats through inducing apoptosis via p53, Bax-dependent caspase-3 activation pathway and down-regulating MLCK overexpression. Iran J Pharm Res. 15:491–499. 2016.PubMed/NCBI
12	Colis L, Peltonen K, Sirajuddin P, Liu H, Sanders S, Ernst G, Barrow JC and Laiho M: DNA intercalator BMH-21 inhibits RNA polymerase I independent of DNA damage response. Oncotarget. 5:4361–4369. 2014. View Article : Google Scholar : PubMed/NCBI
13	Stepiński D: Immunodetection of nucleolar proteins and ultrastructure of nucleoli of soybean root meristematic cells treated with chilling stress and after recovery. Protoplasma. 235:77–89. 2009. View Article : Google Scholar : PubMed/NCBI
14	Chen Z and Xu X: Roles of nucleolin. Focus on cancer and anti-cancer therapy. Saudi Med J. 37:1312–1318. 2016. View Article : Google Scholar : PubMed/NCBI
15	Chopra A, Soni S, Pati H, Kumar D, Diwedi R, Verma D, Vishwakama G, Bakhshi S, Kumar S, Gogia A, et al: Nucleophosmin mutation analysis in acute myeloid leukaemia: Immunohistochemistry as a surrogate for molecular techniques. Indian J Med Res. 143:763–768. 2016. View Article : Google Scholar : PubMed/NCBI
16	Shubina MY, Musinova YR and Sheval EV: Nucleolar methyltransferase fibrillarin: Evolution of structure and functions. Biochemistry (Mosc). 81:941–950. 2016. View Article : Google Scholar : PubMed/NCBI
17	Olausson Holmberg K, Nistér M and Lindström MS: p53 -dependent and -independent nucleolar stress responses. Cells. 1:774–798. 2012. View Article : Google Scholar : PubMed/NCBI
18	Trino S, Iacobucci I, Erriquez D, Laurenzana I, De Luca L, Ferrari A, Ghelli Luserna, Di Rorà A, Papayannidis C, Derenzini E, Simonetti G, et al: Targeting the p53-MDM2 interaction by the small-molecule MDM2 antagonist Nutlin-3a: A new challenged target therapy in adult Philadelphia positive acute lymphoblastic leukemia patients. Oncotarget. 7:12951–12961. 2016.PubMed/NCBI
19	Sun Y, Jin L, Liu JH, Sui YX, Han LL and Shen XL: Interfering EZH2 expression reverses the cisplatin resistance in human ovarian cancer by inhibiting autophagy. Cancer Biother Radiopharm. 31:246–252. 2016. View Article : Google Scholar : PubMed/NCBI
20	Negi SS and Brown P: rRNA synthesis inhibitor, CX-5461, activates ATM/ATR pathway in acute lymphoblastic leukemia, arrests cells in G2 phase and induces apoptosis. Oncotarget. 6:18094–18104. 2015. View Article : Google Scholar : PubMed/NCBI
21	Nicolas E, Parisot P, Pinto-Monteiro C, de Walque R, De Vleeschouwer C and Lafontaine DL: Involvement of human ribosomal proteins in nucleolar structure and p53-dependent nucleolar stress. Nat Commun. 7:113902016. View Article : Google Scholar : PubMed/NCBI
22	Eliopoulos AG and Volarevic S: TPL2-NPM-p53 pathway monitors nucleolar stress. Oncoscience. 2:892–893. 2015.PubMed/NCBI
23	Boulon S, Westman BJ, Hutten S, Boisvert FM and Lamond AI: The nucleolus under stress. Mol Cell. 40:216–227. 2010. View Article : Google Scholar : PubMed/NCBI
24	Sloan KE, Bohnsack MT and Watkins NJ: The 5S RNP couples p53 homeostasis to ribosome biogenesis and nucleolar stress. Cell Rep. 5:237–247. 2013. View Article : Google Scholar : PubMed/NCBI
25	Huang M, Whang P, Lewicki P and Mitchell BS: Cyclopentenyl cytosine induces senescence in breast cancer cells through the nucleolar stress response and activation of p53. Mol Pharmacol. 80:40–48. 2011. View Article : Google Scholar : PubMed/NCBI
26	Russo A, Pagliara V, Albano F, Esposito D, Sagar V, Loreni F, Irace C, Santamaria R and Russo G: Regulatory role of rpL3 in cell response to nucleolar stress induced by Act D in tumor cells lacking functional p53. Cell Cycle. 15:41–51. 2016. View Article : Google Scholar : PubMed/NCBI
27	Qin R, Jiang W and Liu D: Aluminum can induce alterations in the cellular localization and expression of three major nucleolar proteins in root tip cells of Allium cepa var. agrogarum L. Chemosphere. 90:827–834. 2013. View Article : Google Scholar : PubMed/NCBI
28	Parkosadze G, Burkadze G, Mizandari M, Sulakvelidze M and Sanikidze T: Role of proapoptotic p-53 factor in pathogenesis of nonalcoholic hepatosteatosis. Georgian Med News. 2:55–60. 2013.(In Russian).
29	James A, Wang Y, Raje H, Rosby R and DiMario P: Nucleolar stress with and without p53. Nucleus. 5:402–426. 2014. View Article : Google Scholar : PubMed/NCBI
30	Xu J, Han M, Shen J, Guan Q, Bai Z, Lang B, Zhang H, Li Z, Zuo D, Zhang W, et al: 2-Methoxy-5((3,4,5-trimethosyphenyl)seleninyl) phenol inhibits MDM2 and induces apoptosis in breast cancer cells through a p53-independent pathway. Cancer Lett. 383:9–17. 2016. View Article : Google Scholar : PubMed/NCBI
31	Sriraman A, Li Y and Dobbelstein M: Fortifying p53 - beyond Mdm2 inhibitors. Aging (Albany, NY). 8:1836–1837. 2016. View Article : Google Scholar
32	Barone G, Tweddle DA, Shohet JM, Chesler L, Moreno L, Pearson AD and Van Maerken T: MDM2-p53 interaction in paediatric solid tumours: Preclinical rationale, biomarkers and resistance. Curr Drug Targets. 15:114–123. 2014. View Article : Google Scholar : PubMed/NCBI
33	Liang L and Zhang Z: Gambogic acid inhibits malignant melanoma cell proliferation through mitochondrial p66shc/ROS-p53/Bax-mediated apoptosis. Cell Physiol Biochem. 38:1618–1630. 2016. View Article : Google Scholar : PubMed/NCBI
34	Alshatwi AA, Subash-Babu P and Antonisamy P: Violacein induces apoptosis in human breast cancer cells through up regulation of BAX, p53 and down regulation of MDM2. Exp Toxicol Pathol. 68:89–97. 2016. View Article : Google Scholar : PubMed/NCBI
35	Lin Y, Xie G, Xia J, Su D, Liu J, Jiang F and Xu Y: TBMS1 exerts its cytotoxicity in NCI-H460 lung cancer cells through nucleolar stress-induced p53/MDM2-dependent mechanism, a quantitative proteomics study. Biochim Biophys Acta. 1864:204–210. 2016. View Article : Google Scholar : PubMed/NCBI