TRB3 reverses chemotherapy resistance and mediates crosstalk between endoplasmic reticulum stress and AKT signaling pathways in MHCC97H human hepatocellular carcinoma cells

Li,Yang; Zhu,Danxi; Hou,Lidan; Hu,Bin; Xu,Min; Meng,Xiangjun

doi:10.3892/ol.2017.7361

TRB3 reverses chemotherapy resistance and mediates crosstalk between endoplasmic reticulum stress and AKT signaling pathways in MHCC97H human hepatocellular carcinoma cells

Authors:
- Yang Li
- Danxi Zhu
- Lidan Hou
- Bin Hu
- Min Xu
- Xiangjun Meng
View Affiliations

Affiliations: Department of Gastroenterology, Shanghai General Hospital of Nanjing Medical University, Shanghai 200080, P.R. China, Department of Gastroenterology, School of Medicine, Shanghai Ninth People's Hospital of Shanghai Jiaotong University, Shanghai 200011, P.R. China, Department of Gastroenterology, Shanghai General Hospital of Shanghai Jiaotong University, Shanghai 200080, P.R. China
Published online on: November 8, 2017 https://doi.org/10.3892/ol.2017.7361
Pages: 1343-1349

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

Tribbles homolog 3 (TRB3), a type of pseudokinase that contains a consensus serine/threonine kinase catalytic core structure, is upregulated in hepatocellular carcinoma. However, the effect of TRB3 expression in hepatocellular carcinoma and the molecular mechanisms underlying TRB3‑mediated effects on tumorigenesis in hepatocellular carcinoma have not been fully elucidated. The present study focused on the effect of TRB3 expression in MHCC97H hepatocellular carcinoma cells and investigated the underlying molecular mechanisms in MHCC97H cells. In the present study, it was revealed that TRB3 was significantly overexpressed in the MHCC97H hepatocellular carcinoma cell compared with L‑02 normal hepatic cells. Under endoplasmic reticulum (ER) stress induced by thapsigargin and tunicamycin, the levels of TRB3, CCAAT/enhancer binding protein homologous protein (CHOP), protein kinase B (AKT) and phosphorylated (p)AKT expression were upregulated. Furthermore, when the expression of TRB3 was silenced by short hairpin (sh)RNA, the survival of MHCC97H hepatocellular carcinoma cells was increased. Notably, following transduction with lentiviral containing TRB3‑shRNA, cell survival also increased after treatment with chemotherapy drug cisplatin. The present study demonstrated that knockdown of CHOP by shRNA was able to reduce TRB3 expression, and the knockdown of TRB3 markedly increased the level of pAKT. TRB3 was overexpressed in MHCC97H hepatocellular carcinoma cells, particularly under endoplasmic reticulum stress. Knockdown of TRB3 was able to increase cell survival. Therefore, TRB3 expression may induce apoptosis and reverse resistance to chemotherapy in MHCC97H hepatic carcinoma cells. The present study suggests that TRB3 is a key molecule that mediates the crosstalk between ER stress and AKT signal pathways. Furthermore, the present study may provide further insight into the cancer biology of hepatocellular carcinoma and the development of anticancer drugs targeting the ER stress and AKT signaling pathways.

View Figures

View References

1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 2016. View Article : Google Scholar
3	Mizukoshi E, Nakagawa H, Kitahara M, Yamashita T, Arai K, Sunagozaka H, Iida N, Fushimi K and Kaneko S: Phase I trial of multidrug resistance-associated protein 3-derived peptide in patients with hepatocellular carcinoma. Cancer Lett. 369:242–249. 2015. View Article : Google Scholar : PubMed/NCBI
4	Mayumi-Matsuda K, Kojima S, Suzuki H and Sakata T: Identification of a novel kinase-like gene induced during neuronal cell death. Biochem Biophys Res Commun. 258:260–264. 1999. View Article : Google Scholar : PubMed/NCBI
5	Meng X, Leyva ML, Jenny M, Gross I, Benosman S, Fricker B, Harlepp S, Hébraud P, Boos A, Wlosik P, et al: A ruthenium-containing organometallic compound reduces tumor growth through induction of the endoplasmic reticulum stress gene CHOP. Cancer Res. 69:5458–5466. 2009. View Article : Google Scholar : PubMed/NCBI
6	Xu J, Lv S, Qin Y, Shu F, Xu Y, Chen J, Xu BE, Sun X and Wu J: TRB3 interacts with CtIP and is overexpressed in certain cancers. Biochim Biophys Acta. 1770:273–278. 2007. View Article : Google Scholar : PubMed/NCBI
7	Bromati CR, Lellis-Santos C, Yamanaka TS, Nogueira TC, Leonelli M, Caperuto LC, Gorjão R, Leite AR, Anhê GF and Bordin S: UPR induces transient burst of apoptosis in islets of early lactating rats through reduced AKT phosphorylation via ATF4/CHOP stimulation of TRB3 expression. Am J Physiol Regul Integr Comp Physiol. 300:R92–R100. 2011. View Article : Google Scholar : PubMed/NCBI
8	Du K, Herzig S, Kulkarni RN and Montminy M: TRB3: A tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science. 300:1574–1577. 2003. View Article : Google Scholar : PubMed/NCBI
9	Meric-Bernstam F, Akcakanat A, Chen H, Do KA, Sangai T, Adkins F, Gonzalez-Angulo AM, Rashid A, Crosby K, Dong M, et al: PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors. Clin Cancer Res. 18:1777–1789. 2012. View Article : Google Scholar : PubMed/NCBI
10	Samarin J, Laketa V, Malz M, Roessler S, Stein I, Horwitz E, Singer S, Dimou E, Cigliano A, Bissinger M, et al: PI3K/AKT/mTOR-dependent stabilization of oncogenic far-upstream element binding proteins in hepatocellular carcinoma cells. Hepatology. 63:813–826. 2016. View Article : Google Scholar : PubMed/NCBI
11	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
12	Miyoshi N, Ishii H, Mimori K, Takatsuno Y, Kim H, Hirose H, Sekimoto M, Doki Y and Mori M: Abnormal expression of TRIB3 in colorectal cancer: A novel marker for prognosis. Br J Cancer. 101:1664–1670. 2009. View Article : Google Scholar : PubMed/NCBI
13	Wennemers M, Bussink J, Scheijen B, Nagtegaal ID, van Laarhoven HW, Raleigh JA, Varia MA, Heuvel JJ, Rouschop KM, Sweep FC and Span PN: Tribbles homolog 3 denotes a poor prognosis in breast cancer and is involved in hypoxia response. Breast Cancer Res. 13:R822011. View Article : Google Scholar : PubMed/NCBI
14	Carracedo A, Lorente M, Egia A, Blázquez C, García S, Giroux V, Malicet C, Villuendas R, Gironella M, González-Feria L, et al: The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Cancer Cell. 9:301–312. 2006. View Article : Google Scholar : PubMed/NCBI
15	Zhang J, Wen HJ, Guo ZM, Zeng MS, Li MZ, Jiang YE, He XG and Sun CZ: TRB3 overexpression due to endoplasmic reticulum stress inhibits AKT kinase activation of tongue squamous cell carcinoma. Oral Oncol. 47:934–939. 2011. View Article : Google Scholar : PubMed/NCBI
16	Ord T, Ord D, Kõivomägi M, Juhkam K and Ord T: Human TRB3 is upregulated in stressed cells by the induction of translationally efficient mRNA containing a truncated 5′-UTR. Gene. 444:24–32. 2009. View Article : Google Scholar : PubMed/NCBI
17	Yeo W, Mok TS, Zee B, Leung TW, Lai PB, Lau WY, Koh J, Mo FK, Yu SC, Chan AT, et al: A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst. 97:1532–1538. 2005. View Article : Google Scholar : PubMed/NCBI
18	Wang WA, Groenendyk J and Michalak M: Endoplasmic reticulum stress associated responses in cancer. Biochim Biophys Acta. 1843:2143–2149. 2014. View Article : Google Scholar : PubMed/NCBI
19	Mondal D, Mathur A and Chandra PK: Tripping on TRIB3 at the junction of health, metabolic dysfunction and cancer. Biochimie. 124:34–52. 2016. View Article : Google Scholar : PubMed/NCBI
20	Ohoka N, Yoshii S, Hattori T, Onozaki K and Hayashi H: TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J. 24:1243–1255. 2005. View Article : Google Scholar : PubMed/NCBI
21	Dim DC, Jiang F, Qiu Q, Li T, Darwin P, Rodgers WH and Peng HQ: The usefulness of S100P, mesothelin, fascin, prostate stem cell antigen and 14-3-3 sigma in diagnosing pancreatic adenocarcinoma in cytological specimens obtained by endoscopic ultrasound guided fine-needle aspiration. Diagn Cytopathol. 42:193–199. 2014. View Article : Google Scholar : PubMed/NCBI