Cisplatin-induced regulation of signal transduction pathways and transcription factors in p53-mutated subclone variants of hepatoma cells: Potential application for therapeutic targeting

Kuo,Jinn‑Rung; Shang,Hung‑Sheng; Ho,Chun‑Te; Lai,Kun‑Goung; Liu,Tsan‑Zon; Chen,Yin‑Ju; Chiou,Jeng‑Fong

doi:10.3892/ol.2016.5181

Cisplatin-induced regulation of signal transduction pathways and transcription factors in p53-mutated subclone variants of hepatoma cells: Potential application for therapeutic targeting

Authors:
- Jinn‑Rung Kuo
- Hung‑Sheng Shang
- Chun‑Te Ho
- Kun‑Goung Lai
- Tsan‑Zon Liu
- Yin‑Ju Chen
- Jeng‑Fong Chiou
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Affiliations: Department of Neurosurgery, Chi‑Mei Medical Center, Tainan 71004, Taiwan, R.O.C., Division of Clinical Pathology, Department of Pathology, National Defense Medical Center, Tri‑Service General Hospital, Taipei 11490, Taiwan, R.O.C., Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C., Department of Radiation Oncology, Tungs' Taichung Metro Harbor Hospital, Taichung 43503, Taiwan, R.O.C., Translational Research Laboratory, Cancer Center, Taipei Medical University, Taipei 11031, Taiwan, R.O.C., Department of Radiation Oncology, Taipei Medical University Hospital, Taipei 11031, Taiwan, R.O.C.
Published online on: September 23, 2016 https://doi.org/10.3892/ol.2016.5181
Pages: 3723-3730
Copyright: © Kuo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Cisplatin is commonly recognized as a DNA-damaging drug; however, its versatile antitumor effects have been demonstrated to extend beyond this narrow functional attribute. The present study determined how cisplatin regulates alternative pathways and transcription factors to exert its additional antitumor actions. Cisplatin was observed to be able to trigger an endoplasmic reticulum stress response through aggravated nitrosative stress coupled to perturbed mitochondrial calcium (Ca2+) homeostasis, which substantially downregulated glucose‑regulated protein (GRP) 78 expression by suppressing the cleavage of activating transcription factor (ATF) 6α (90 kDa) to its active 50 kDa subunit. Concomitantly, the ATF4‑ATF3‑C/emopamil binding protein homologous protein axis was activated by cisplatin, which triggered cellular glutathione (GSH) depletion by strongly inhibiting γ‑glutamylcysteine synthetase heavy chain (γ‑GCSh), a key enzyme in GSH biosynthesis. The present study also demonstrated that cisplatin substantially inhibited β‑catenin, causing a marked downregulation of survivin and B‑cell lymphoma (Bcl)‑2. Taken together, the present results uncovered a novel mechanism of cisplatin that could simultaneously trigger the inhibition of three prominent antiapoptotic effector molecules (Bcl‑2, survivin and GRP78) and effectively promote GSH depletion by inhibiting γ‑GCSh. These newly discovered functional attributes of cisplatin can provide an avenue for novel combined therapeutic strategies to kill hepatocellular carcinoma cells effectively.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Lim YS, Han S, Heo NY, Shim JH, Lee HC and Suh DJ: Mortality, liver transplantation, and hepatocellular carcinoma among patients with chronic hepatitis B treated with entecavir vs lamivudine. Gastroenterology. 147:152–161. 2014. View Article : Google Scholar : PubMed/NCBI
3	Tabrizian P, Roayaie S and Schwartz ME: Current management of hepatocellular carcinoma. World J Gastroenterol. 20:10223–10237. 2014. View Article : Google Scholar : PubMed/NCBI
4	Kelland L: The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 7:573–584. 2007. View Article : Google Scholar : PubMed/NCBI
5	Stewart DJ: Mechanisms of resistance to cisplatin and carboplatin. Crit Rev Oncol Hematol. 63:12–31. 2007. View Article : Google Scholar : PubMed/NCBI
6	Vaisman A, Varchenko M, Said I and Chaney SG: Cell cycle changes associated with formation of Pt-DNA adducts in human ovarian carcinoma cells with different cisplatin sensitivity. Cytometry. 27:54–64. 1997. View Article : Google Scholar : PubMed/NCBI
7	Burger H, Nooter K, Boersma AW, Kortland CJ and Stoter G: Lack of correlation between cisplatin-induced apoptosis, p53 status and expression of Bcl-2 family proteins in testicular germ cell tumour cell lines. Int J Cancer. 73:592–599. 1997. View Article : Google Scholar : PubMed/NCBI
8	Mandic A, Hansson J, Linder S and Shoshan MC: Cisplatin induces endoplasmic reticulum stress and nucleus-independent apoptotic signaling. J Biol Chem. 278:9100–9106. 2003. View Article : Google Scholar : PubMed/NCBI
9	Baek SM, Kwon CH, Kim JH, Woo JS, Jung JS and Kim YK: Differential roles of hydrogen peroxide and hydroxyl radical in cisplatin-induced cell death in renal proximal tubular epithelial cells. J Lab Clin Med. 142:178–186. 2003. View Article : Google Scholar : PubMed/NCBI
10	Huang Y, Zhou S, Qui L, Wu J and Xu C: Effects of zinc gluconate on nephrotoxicity and glutathione metabolism disorder induced by cis-platin in mice. Drug Metabol Drug Interact. 14:41–46. 1997. View Article : Google Scholar : PubMed/NCBI
11	Kuo TC, Chang PY, Huang SF, Chou CK and Chao CC: Knockdown of HURP inhibits the proliferation of hepacellular carcinoma cells via downregulation of gankyrin and accumulation of p53. Biochem Pharmacol. 83:758–768. 2012. View Article : Google Scholar : PubMed/NCBI
12	Vichai V and Kirtikara K: Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc. 1:1112–1116. 2006. View Article : Google Scholar : PubMed/NCBI
13	Chen CY, Liu TZ, Liu YW, Tseng WC, Liu RH, Lu FJ, Lin YS, Kuo SH and Chen CH: 6-shogaol (alkanone from ginger) induces apoptotic cell death of human hepatoma p53 mutant Mahlavu subline via an oxidative stress-mediated caspase-dependent mechanism. J Agric Food Chem. 55:948–954. 2007. View Article : Google Scholar : PubMed/NCBI
14	Matouk IJ, Mezan S, Mizrahi A, Ohana P, Abu-Lail R, Fellig Y, Degroot N, Galun E and Hochberg A: The oncofetal H19 RNA connection: Hypoxia, p53 and cancer. Biochim Biophys Acta. 1803:443–451. 2010. View Article : Google Scholar : PubMed/NCBI
15	Wu CH, Uen YH, Ho CT, Tseng YT, Liu TZ, Chiou JF and Leung SW: Constitutive overexpression of Bcl-2, Survivin and ER stress chaperone GRP-78 confers intrinsic radioresistance in human hepatocellular carcinoma cells: Insight into the mechanistic pathways involved*. J Cancer Ther. 4:3992013. View Article : Google Scholar
16	Hsu HC, Chiou JF, Wang YH and Chen CH, Mau SY, Ho CT, Change PJ, Liu TZ and Chen CH: Folate deficiency triggers an oxidative-nitrosative stress-mediated apoptotic cell death and impedes insulin biosynthesis in RINm5F pancreatic islet beta-cells: Relevant to the pathogenesis of diabetes. PLoS One. 8:e779312013. View Article : Google Scholar : PubMed/NCBI
17	Griffith OW and Meister A: Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-n-butyl homocysteine sulfoximine). J Biol Chem. 254:7558–7560. 1979.PubMed/NCBI
18	Lee HC, Kim M and Wands JR: Wnt/Frizzled signaling in hepatocellular carcinoma. Front Biosci. 11:1901–1915. 2006. View Article : Google Scholar : PubMed/NCBI
19	Takigawa Y and Brown AM: Wnt signaling in liver cancer. Curr Drug Targets. 9:1013–1024. 2008. View Article : Google Scholar : PubMed/NCBI
20	Kim Y, Jang M, Lim S, Won H, Yoon KS, Park JH, Kim HJ, Kim BH, Park WS, Ha J and Kim SS: Role of cyclophilin B in tumorigenesis and cisplatin resistance in hepatocellular carcinoma in humans. Hepatology. 54:1661–1678. 2011. View Article : Google Scholar : PubMed/NCBI
21	Lim SC, Choi JE, Kang HS and Han SI: Ursodeoxycholic acid switches oxaliplatin-induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53-caspase 8 pathway in HepG2 hepatocellular carcinoma. Int J Cancer. 126:1582–1595. 2010.PubMed/NCBI
22	Friedman SL, Shaulian E, Littlewood T, Resnitzky D and Oren M: Resistance to p53-mediated growth arrest and apoptosis in Hep 3B hepatoma cells. Oncogene. 15:63–70. 1997. View Article : Google Scholar : PubMed/NCBI
23	Rabik CA, Fishel ML, Holleran JL, Kasza K, Kelley MR, Egorin MJ and Dolan ME: Enhancement of cisplatin [cis-diammine dichloroplatinum (II)] cytotoxicity by O6-benzylguanine involves endoplasmic reticulum stress. J Pharmacol Exp Ther. 327:442–452. 2008. View Article : Google Scholar : PubMed/NCBI
24	Ahmad M, Hahn IF and Chatterjee S: GRP78 up-regulation leads to hypersensitization to cisplatin in A549 lung cancer cells. Anticancer Res. 34:3493–3500. 2014.PubMed/NCBI
25	Xu W, Liu L, Charles IG and Moncada S: Nitric oxide induces coupling of mitochondrial signalling with the endoplasmic reticulum stress response. Nat Cell Biol. 6:1129–1134. 2004. View Article : Google Scholar : PubMed/NCBI
26	Zhao S, Xiong Z, Mao X, Meng D, Lei Q, Li Y, Deng P, Chen M, Tu M, Lu X, et al: Atmospheric pressure room temperature plasma jets facilitate oxidative and nitrative stress and lead to endoplasmic reticulum stress dependent apoptosis in HepG2 cells. PLoS One. 8:e736652013. View Article : Google Scholar : PubMed/NCBI
27	Xu Y, Wang C and Li Z: A new strategy of promoting cisplatin chemotherapeutic efficiency by targeting endoplasmic reticulum stress. Mol Clin Oncol. 2:3–7. 2014.PubMed/NCBI
28	Verras M, Papandreou I, Lim AL and Denko NC: Tumor hypoxia blocks Wnt processing and secretion through the induction of endoplasmic reticulum stress. Mol Cell Biol. 28:7212–7224. 2008. View Article : Google Scholar : PubMed/NCBI
29	Chiu CC, Lee LY, Li YC, Chen YJ, Lu YC, Li YL, Wang HM, Chang JT and Cheng AJ: Grp78 as a therapeutic target for refractory head-neck cancer with CD24(−)CD44(+) stemness phenotype. Cancer Gene Ther. 20:606–615. 2013. View Article : Google Scholar : PubMed/NCBI
30	Lin JA, Fang SU, Su CL, Hsiao CJ, Chang CC, Lin YF and Cheng CW: Silencing glucose-regulated protein 78 induced renal cell carcinoma cell line G1 cell-cycle arrest and resistance to conventional chemotherapy. Urol Oncol. 32:29.e1–e11. 2014. View Article : Google Scholar
31	St Germain C, O'Brien A and Dimitroulakos J: Activating Transcription Factor 3 regulates in part the enhanced tumour cell cytotoxicity of the histone deacetylase inhibitor M344 and cisplatin in combination. Cancer Cell Int. 10:322010. View Article : Google Scholar : PubMed/NCBI
32	Yang N, Zhang H, Si-Ma H, Fu Y, Zhao W, Li D and Yang G: Dexamethasone decreases hepatocellular carcinoma cell sensitivity to cisplatin-induced apoptosis. Hepatogastroenterology. 58:1730–1735. 2011. View Article : Google Scholar : PubMed/NCBI
33	Liu G, Su L, Hao X, Zhong N, Zhong D, Singhal S and Liu X: Salermide up-regulates death receptor 5 expression through the ATF4-ATF3-CHOP axis and leads to apoptosis in human cancer cells. J Cell Mol Med. 16:1618–1628. 2012. View Article : Google Scholar : PubMed/NCBI
34	Dong D, Ni M, Li J, Xiong S, Ye W, Virrey JJ, Mao C, Ye R, Wang M, Pen L, et al: Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. Cancer Res. 68:498–505. 2008. View Article : Google Scholar : PubMed/NCBI
35	Altieri DC: Molecular circuits of apoptosis regulation and cell division control: The survivin paradigm. J Cell Biochem. 92:656–663. 2004. View Article : Google Scholar : PubMed/NCBI
36	Tien LT, Ito M, Nakao M, Niino D, Serik M, Nakashima M, Wen CY, Yatsuhashi H and Ishibashi H: Expression of beta-catenin in hepatocellular carcinoma. World J Gastroenterol. 11:2398–2401. 2005. View Article : Google Scholar : PubMed/NCBI
37	Thompson MD and Monga SP: WNT/beta-catenin signaling in liver health and disease. Hepatology. 45:1298–1305. 2007. View Article : Google Scholar : PubMed/NCBI