Administration of 4‑hexylresorcinol increases p53‑mediated transcriptional activity in oral cancer cells with the p53 mutation

Kang,Yei-Jin; Yang,Won-Geun; Chae,Weon-Sik; Kim,Dae-Won; Kim,Seong-Gon; Rotaru,Horatiu

doi:10.3892/or.2022.8375

Administration of 4‑hexylresorcinol increases p53‑mediated transcriptional activity in oral cancer cells with the p53 mutation

Authors:
- Yei-Jin Kang
- Won-Geun Yang
- Weon-Sik Chae
- Dae-Won Kim
- Seong-Gon Kim
- Horatiu Rotaru
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Affiliations: Department of Oral and Maxillofacial Surgery, Gangneung‑Wonju National University, Gangneung, Gangwon-do 25457, Republic of Korea, Daegu Center, Korea Basic Science Institute, Daegu 41566, Republic of Korea, Department of Oral Biochemistry, College of Dentistry, Gangneung‑Wonju National University, Gangneung, Gangwon-do 25457, Republic of Korea, Department of Cranio‑Maxillofacial Surgery, ‘Iuliu Hatieganu’ University of Medicine and Pharmacy, Cluj‑Napoca 400000, Romania
Published online on: July 20, 2022 https://doi.org/10.3892/or.2022.8375
Article Number: 160
Copyright: © Kang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The p53 mutation is inherent in over 50% of human cancers. In head and neck squamous cell carcinoma, the p53 mutation is associated with a poor prognosis. 4‑Hexylresorcinol (4HR) is a pharmacologic chaperone. The present study aimed to investigate the effect of 4HR on p53 transcriptional activity in oral carcinoma cells with p53 mutations. To identify conformational changes induced by 4HR administration, peptides including the DNA‑binding domain from mutant and wild‑type p53 were synthesized, and Fourier transform infrared spectroscopy was performed. To determine the effect of 4HR on p53 mutant carcinoma cells, western blot analysis, p53 transcriptional activity analysis, MTT assay and apoptosis immunocytochemistry were performed. The YD‑15 cell line has a mutation in the DNA binding domain of p53 (Glu258Ala). When p53 Ala‑258 was coupled by 4HR, the p53 Ala‑258 structure lost its original conformation and approached a conformation similar to that of p53 Glu‑258. In the cell experiments, 4HR administration to p53 mutant cells increased p53 transcriptional activity and the expression levels of apoptosis‑associated proteins such as B‑cell lymphoma 2 (BCL2), BCL2‑associated X (BAX) and BCL2‑associated agonist of cell death (BAD). Accordingly, 4HR administration on YD‑15 cells decreased cell viability and increased apoptosis. In conclusion, 4HR is a potential substance for use in the recovery of loss‑of‑function in mutant p53 as a pharmacologic chaperone.

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1	Lane DP: Cancer. p53, guardian of the genome. Nature. 358:15–16. 1992. View Article : Google Scholar : PubMed/NCBI
2	Levine AJ: p53, the cellular gatekeeper for growth and division. Cell. 88:323–331. 1997. View Article : Google Scholar
3	Xia Z, Kon N, Gu AP, Tavana O and Gu W: Deciphering the acetylation code of p53 in transcription regulation and tumor suppression. Oncogene. 41:3039–3050. 2022. View Article : Google Scholar : PubMed/NCBI
4	Pecorino L: Molecular biology of Cancer. Oxford University Press; Oxford: 2016
5	Lee JH, Kim HS, Lee SJ and Kim KT: Stabilization and activation of p53 induced by Cdk5 contributes to neuronal cell death. J Cell Sci. 120:2259–2271. 2007. View Article : Google Scholar
6	Brooks CL and Gu W: Ubiquitination, phosphorylation and acetylation: The molecular basis for p53 regulation. Curr Opin Cell Biol. 15:164–171. 2003. View Article : Google Scholar
7	Peltonen JK, Helppi HM, Pääkkö P, Turpeenniemi-Hujanen T and Vähäkangas KH: p53 in head and neck cancer: Functional consequences and environmental implications of TP53 mutations. Head Neck Oncol. 2:362010. View Article : Google Scholar
8	Lindemann A, Takahashi H, Patel A, Osman A and Myers J: Targeting the DNA damage response in OSCC with TP 53 mutations. J Dent Res. 97:635–644. 2018. View Article : Google Scholar : PubMed/NCBI
9	de Bakker T, Journe F, Descamps G, Saussez S, Dragan T, Ghanem G, Krayem M and Van Gestel D: Restoring p53 function in head and neck squamous cell carcinoma to improve treatments. Front Oncol. 11:7999932022. View Article : Google Scholar
10	Kaida A and Iwakuma T: Regulation of p53 and cancer signaling by heat shock protein 40/J-domain protein family members. Int J Mol Sci. 22:135272021. View Article : Google Scholar
11	Kanapathipillai M: Treating p53 mutant aggregation-associated cancer. Cancers (Basel). 10:1542018. View Article : Google Scholar
12	Muller PA and Vousden KH: Mutant p53 in cancer: New functions and therapeutic opportunities. Cancer Cell. 25:304–317. 2014. View Article : Google Scholar
13	Lee EJ, Kim J, Lee SA, Kim EJ, Chun YC, Ryu MH and Yook JI: Characterization of newly established oral cancer cell lines derived from six squamous cell carcinoma and two mucoepidermoid carcinoma cells. Exp Mol Med. 37:379–390. 2005. View Article : Google Scholar : PubMed/NCBI
14	Lambert JM, Gorzov P, Veprintsev DB, Söderqvist M, Segerbäck D, Bergman J, Fersht AR, Hainaut P, Wiman KG and Bykov VJ: PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell. 15:376–388. 2009. View Article : Google Scholar
15	Chen HM, Lee YH and Wang YJ: ROS-triggered signaling pathways involved in the cytotoxicity and tumor promotion effects of pentachlorophenol and tetrachlorohydroquinone. Chem Res Toxicol. 28:339–350. 2015. View Article : Google Scholar
16	Kim SG: 4-Hexylresorcinol: Pharmacologic chaperone and its application for wound healing. Maxillofac Plast Reconstr Surg. 44:52022. View Article : Google Scholar : PubMed/NCBI
17	Lee IS, Chang JH, Kim DW, Kim SG and Kim TW: The effect of 4-hexylresorinol administration on NAD+ level and SIRT activity in Saos-2 cells. Maxillofac Plast Reconstr Surg. 43:392021. View Article : Google Scholar : PubMed/NCBI
18	Kim JY, Kweon HY, Kim DW, Choi JY and Kim SG: 4-Hexylresorcinol inhibits class I histone deacetylases in human umbilical cord endothelial cells. Appl Sci. 11:34862021. View Article : Google Scholar
19	Kim DW, Jo YY, Garagiola U, Choi JY, Kang YJ, Oh JH and Kim SG: Increased level of vascular endothelial growth factors by 4-hexylresorcinol is mediated by transforming growth factor-β1 and accelerates capillary regeneration in the burns in diabetic animals. Int J Mol Sci. 21:34732020. View Article : Google Scholar
20	Jiménez-Uribe AP, Gómez-Sierra T, Aparicio-Trejo OE, Orozco-Ibarra M and Pedraza-Chaverri J: Backstage players of fibrosis: NOX4, mTOR, HDAC, and S1P; companions of TGF-β. Cell Signal. 87:1101232021. View Article : Google Scholar
21	Kim SG, JeonG JH, Park YW, Song JY, Kim AS, Choi JY and Chae WS: 4-Hexylresorcinol inhibits transglutaminase-2 activity and has synergistic effects along with cisplatin in KB cells. Oncol Rep. 25:1597–1602. 2011.PubMed/NCBI
22	Kim SG, Lee SW, Park YW, Jeong JH and Choi JY: 4-hexylresorcinol inhibits NF-κB phosphorylation and has a synergistic effect with cisplatin in KB cells. Oncol Rep. 26:1527–1532. 2011.PubMed/NCBI
23	Xue L, Zhou B, Liu X, Qiu W, Jin Z and Yen Y: Wild-type p53 regulates human ribonucleotide reductase by protein-protein interaction with p53R2 as well as hRRM2 subunits. Cancer Res. 63:980–986. 2003.PubMed/NCBI
24	Luo J, Su F, Chen D, Shiloh A and Gu W: Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature. 408:377–381. 2000. View Article : Google Scholar : PubMed/NCBI
25	Zhang Y, Dong Y, Wu X, Lu Y, Xu Z, Knapp A, Yue Y, Xu T and Xie Z: The mitochondrial pathway of anesthetic isoflurane-induced apoptosis. J Biol Chem. 285:4025–4037. 2010. View Article : Google Scholar : PubMed/NCBI
26	Shen Y, Maupetit J, Derreumaux P and Tufféry P: Improved PEP-FOLD approach for peptide and miniprotein structure prediction. J Chem Theory Comput. 10:4745–4758. 2014. View Article : Google Scholar
27	Thévenet P, Shen Y, Maupetit J, Guyon F, Derreumaux P and Tufféry P: PEP-FOLD: An updated de novo structure prediction server for both linear and disulfide bonded cyclic peptides. Nucleic Acids Res. 40:(Web Server Issue). W288–W293. 2012. View Article : Google Scholar
28	Kong J and Yu S: Fourier transform infrared spectroscopic analysis of protein secondary structures. Acta Biochim Biophys Sin (Shanghai). 39:549–559. 2007. View Article : Google Scholar : PubMed/NCBI
29	Jo YY, Kweon H, Kim DW, Baek K, Kim MK, Kim SG, Chae WS, Choi JY and Rotaru H: Bone regeneration is associated with the concentration of tumour necrosis factor-α induced by sericin released from a silk mat. Sci Rep. 7:155892017. View Article : Google Scholar : PubMed/NCBI
30	Jo YY, Kweon H, Kim DW, Baek K, Chae WS, Kang YJ, Oh JH, Kim SG and Garagiola U: Silk sericin application increases bone morphogenic protein-2/4 expression via a toll-like receptor-mediated pathway. Int J Biol Macromol. 190:607–617. 2021. View Article : Google Scholar
31	Buonocore G, Perrone S and Tataranno ML: Oxygen toxicity: Chemistry and biology of reactive oxygen species. Int J Biol Macromol. 15:186–190. 2010.
32	Yen GC, Duh PD and Lin CW: Effects of resveratrol and 4-hexylresorcinol on hydrogen peroxide-induced oxidative DNA damage in human lymphocytes. Free Radic Res. 37:509–514. 2003. View Article : Google Scholar : PubMed/NCBI
33	Guandalini E, Ioppolo A, Mantovani A, Stacchini P and Giovannini C: 4-Hexylresorcinol as inhibitor of shrimp melanosis: Efficacy and residues studies; evaluation of possible toxic effect in a human intestinal in vitro model (Caco-2); preliminary safety assessment. Food Addit Contam. 15:171–180. 1998. View Article : Google Scholar : PubMed/NCBI
34	Synnott NC, O'Connell D, Crown J and Duffy MJ: COTI-2 reactivates mutant p53 and inhibits growth of triple-negative breast cancer cells. Breast Cancer Res Treat. 179:47–56. 2020. View Article : Google Scholar
35	Lindemann A, Patel AA, Silver NL, Tang L, Liu Z, Wang L, Tanaka N, Rao X, Takahashi H, Maduka NK, et al: COTI-2, a novel thiosemicarbazone derivative, exhibits antitumor activity in HNSCC through p53-dependent and-independent mechanisms. Clin Cancer Res. 25:5650–5662. 2019. View Article : Google Scholar : PubMed/NCBI
36	Gao L, Yu L, Li CM, Li Y, Jia BL and Zhang B: Karyopherin α2 induces apoptosis in tongue squamous cell carcinoma CAL-27 cells through the p53 pathway. Oncol Rep. 35:3357–3362. 2016. View Article : Google Scholar : PubMed/NCBI
37	Lee IS, Kim DW, Oh JH, Lee SK, Choi JY, Kim SG and Kim TW: Effects of 4-hexylresorcinol on craniofacial growth in rats. Int J Mol Sci. 22:89352021. View Article : Google Scholar
38	Kim JY, Kim DW, Lee SK, Choi JY, Che X, Kim SG and Garagiola U: Increased expression of TGF-β1 by 4-hexylresorcinol is mediated by endoplasmic reticulum and mitochondrial stress in human umbilical endothelial vein cells. Appl Sci. 11:91282021. View Article : Google Scholar
39	Hori M, Suzuki K, Udono MU, Yamauchi M, Mine M, Watanabe M, Kondo S and Hozumi Y: Establishment of ponasterone A-inducible the wild-type p53 protein-expressing clones from HSC-1 cells, cell growth suppression by p53 expression and the suppression mechanism. Arch Dermatol Res. 301:631–646. 2009. View Article : Google Scholar : PubMed/NCBI
40	Kashiwazaki H: Detectability and diagnostic criteria of p53 gene mutations in human oral squamous cell carcinoma using yeast functional assay. Hokkaido Igaku Zasshi. 72:211–224. 1997.(In Japanese).
41	Ichwan SJ, Yamada S, Sumrejkanchanakij P, Ibrahim-Auerkari E, Eto K and Ikeda MA: Defect in serine 46 phosphorylation of p53 contributes to acquisition of p53 resistance in oral squamous cell carcinoma cells. Oncogene. 25:1216–1224. 2006. View Article : Google Scholar : PubMed/NCBI