Rab‑like protein 1 A is upregulated by cisplatin treatment and partially inhibits chemoresistance by regulating p53 activity

Chen,Changjin; Zhao,Ziyi; Tang,Shiyun; Zhang,Cuiwei

doi:10.3892/ol.2018.9205

Rab‑like protein 1 A is upregulated by cisplatin treatment and partially inhibits chemoresistance by regulating p53 activity

Authors:
- Changjin Chen
- Ziyi Zhao
- Shiyun Tang
- Cuiwei Zhang
View Affiliations

Affiliations: Central Laboratory, The Teaching Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China, Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
Published online on: July 24, 2018 https://doi.org/10.3892/ol.2018.9205
Pages: 4593-4599

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

Rab‑like protein 1 A (RBEL1A), which is a predominant isoform of RBEL1, has been identified to serve an important function in breast tumorigenesis and may be upregulated in breast tumor cells. RBEL1A may block the transcriptional activity of p53, which is important in the induction of cisplatin sensitivity. Previous studies supported the association between the induction of chemoresistance and the inhibition of p53 by RBEL1A. However, the response of RBEL1A to chemotreatment and its interaction with p53 remains to be investigated. The present study revealed that the cisplatin treatment induced the expression of RBEL1A in MCF‑7 cells. Consistent with previous studies, the present study demonstrated that cisplatin treatment and RBEL1A overexpression blocked the oligomerization of p53 in MCF‑7 cells and led to a decrease of the transcriptional activity of p53 and its downstream target gene p21. Additionally, upregulation of RBEL1A decreased the protein level of p53 by promoting the ubiquitination of p53. A cytotoxicity assay demonstrated that upregulation of RBEL1A partially contributed to chemosensitivity via inhibiting p53 in MCF‑7 cells. A pG13L (p53‑responsive reporter plasmid) luciferase reporter and co‑immunoprecipitation assay revealed that upregulation of RBEL1A led to an inhibition of the transcriptional activity of p53 or its target gene p21. Analysis of cellular proliferation, cell cycle and invasion also confirmed the regulatory activity of RBEL1A on the malignancy of breast cancer cells. Taken together, these results suggest that the induction of RBEL1A following cisplatin treatment may partially inhibit chemosensitivity in a p53‑dependent manner.

View Figures

View References

1	Montalbano J, Lui K, Sheikh MS and Huang Y: Identification and characterization of RBEL1 subfamily of GTPases in the Ras superfamily involved in cell growth regulation. J Biol Chem. 284:18129–18142. 2009. View Article : Google Scholar : PubMed/NCBI
2	Lui K, An J, Montalbano J, Shi J, Corcoran C, He Q, Sun H, Sheikh MS and Huang Y: Negative regulation of p53 by Ras superfamily protein RBEL1A. J Cell Sci. 126:2436–2445. 2013. View Article : Google Scholar : PubMed/NCBI
3	Montalbano J, Jin W, Sheikh MS and Huang Y: RBEL1 is a novel gene that encodes a nucleocytoplasmic Ras superfamily GTP-binding protein and is overexpressed in breast cancer. J Biol Chem. 282:37640–37649. 2007. View Article : Google Scholar : PubMed/NCBI
4	Levine AJ, Hu W and Feng Z: The P53 pathway: What questions remain to be explored? Cell Death Differ. 13:1027–1036. 2006. View Article : Google Scholar : PubMed/NCBI
5	Jiang L, Sheikh MS and Huang Y: Decision making by p53: Life versus death. Mol Cell Pharmacol. 2:69–77. 2010.PubMed/NCBI
6	Duffy MJ, Synnott NC, McGowan PM, Crown J, O'Connor D and Gallagher WM: p53 as a target for the treatment of cancer. Cancer Treat Rev. 40:1153–1160. 2014. View Article : Google Scholar : PubMed/NCBI
7	Ozaki T and Nakagawara A: p53: The attractive tumor suppressor in the cancer research field. J Biomed Biotechnol. 2011:6039252011. View Article : Google Scholar : PubMed/NCBI
8	Higashimoto Y, Asanomi Y, Takakusagi S, Lewis MS, Uosaki K, Durell SR, Anderson CW, Appella E and Sakaguchi K: Unfolding, aggregation, and amyloid formation by the tetramerization domain from mutant p53 associated with lung cancer. Biochemistry. 45:1608–1619. 2006. View Article : Google Scholar : PubMed/NCBI
9	van Dieck J, Fernandez-Fernandez MR, Veprintsev DB and Fersht AR: Modulation of the oligomerization state of p53 by differential binding of proteins of the S100 family to p53 monomers and tetramers. J Biol Chem. 284:13804–13811. 2009. View Article : Google Scholar : PubMed/NCBI
10	Lin J, Yang Q, Yan Z, Markowitz J, Wilder PT, Carrier F and Weber DJ: Inhibiting S100B restores p53 levels in primary malignant melanoma cancer cells. J Biol Chem. 279:34071–34077. 2004. View Article : Google Scholar : PubMed/NCBI
11	Foo RS, Nam YJ, Ostreicher MJ, Metzl MD, Whelan RS, Peng CF, Ashton AW, Fu W, Mani K, Chin SF, et al: Regulation of p53 tetramerization and nuclear export by ARC. Proc Natl Acad Sci USA. 104:20826–20831. 2007. View Article : Google Scholar : PubMed/NCBI
12	Lui K, Sheikh MS and Huang Y: Regulation of p53 oligomerization by Ras superfamily protein RBEL1A. Genes Cancer. 6:307–316. 2015.PubMed/NCBI
13	Boulikas T and Vougiouka M: Cisplatin and platinum drugs at the molecular level. (Review). Oncol Rep. 10:1663–1682. 2003.PubMed/NCBI
14	Stavridi ES, Chehab NH, Caruso LC and Halazonetis TD: Change in oliogmerization specificity of the p53 tetramerization domain by hydrophobic amino acid substitutions. Protein Sci. 8:1773–1779. 1999. View Article : Google Scholar : PubMed/NCBI
15	Fernandez-Fernandez MR, Veprintsev DB and Fersht AR: Proteins of the S100 family regulate the oligomerization of p53 tumor suppressor. Proc Natl Acad Sci USA. 102:4735–4740. 2005. View Article : Google Scholar : PubMed/NCBI
16	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
17	Tallarida RJ and Murray RB: Manual of pharmacologic calculations with computer programs. Springer Publisher; pp. 100–104. 1986
18	Sekine H, Chen N, Sato K, Saiki Y, Yoshino Y, Umetsu Y, Jin G, Nagase H, Gu Z, Fukushige S, Sunamura M and Horii A: S100A4, frequently overexpressed in various human cancers, accelerates cell motility in pancreatic cells. Biochem Biophys Res Commun. 429:214–219. 2012. View Article : Google Scholar : PubMed/NCBI
19	Maletzki C, Bodammer P, Breitrück A and Kerkhoff C: S100 proteins as diagnostic and prognostic markers in colorectal and hepatocellular carcinoma. Hepat Mon. 12(10 HCC): e72402012.PubMed/NCBI
20	Mercier I, Vuolo M, Jasmin JF, Medina CM, Williams M, Mariadason JM, Qian H, Xue X, Pestell RG, Lisanti MP and Kitsis RN: ARC (apoptosis repressor with caspase recruitment domain) is a novel marker of human colon cancer. Cell Cycle. 7:1640–1647. 2008. View Article : Google Scholar : PubMed/NCBI
21	Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P and Olivier M: Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: Lessons from recent developments in the IARC TP53. Hum Mutat. 28:622–629. 2007. View Article : Google Scholar : PubMed/NCBI
22	Kelavkar UP and Badr KF: Effects of mutant p53 expression on human 15-lipoxygenase-promoter activity and murine 12/15-lipoxygenase gene expression: Evidence that 15-lipoxygenase is a mutator gene. Proc Natl Acad Sci USA. 96:4378–4383. 1999. View Article : Google Scholar : PubMed/NCBI
23	Reddy N, Everhart A, Eling T and Glasgow W: Characterization of a 15-lipoxygenase in human breast carcinoma BT-20 cells: Stimulation of 13-HODE formation by TGF alpha/EGF. Biochem Biophys Res Commun. 231:111–116. 1997. View Article : Google Scholar : PubMed/NCBI
24	Gallagher EJ and LeRoith D: Minireview: IGF, insulin, and cancer. Endocrinology. 152:2546–2551. 2011. View Article : Google Scholar : PubMed/NCBI