Inhibition of the PI3K/Akt signaling pathway reverses sorafenib‑derived chemo‑resistance in hepatocellular carcinoma

Zhang,Hao; Wang,Qingqing; Liu,Jun; Cao,Haoqiang

doi:10.3892/ol.2018.8536

Inhibition of the PI3K/Akt signaling pathway reverses sorafenib‑derived chemo‑resistance in hepatocellular carcinoma

Authors:
- Hao Zhang
- Qingqing Wang
- Jun Liu
- Haoqiang Cao
View Affiliations

Affiliations: Department of General Surgery, The First Hospital of Jiaxing, Jiaxing, Zhejiang 314001, P.R. China
Published online on: April 18, 2018 https://doi.org/10.3892/ol.2018.8536
Pages: 9377-9384

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

Long‑term sorafenib treatment triggers resistance to chemotherapy in patients with hepatocellular carcinoma (HCC). In order to investigate the mechanisms of sorafenib resistance in HCC, the aim of the present study was to develop a resistant human liver cell line via long‑term exposure to sorafenib. The cytotoxicity cell counting kit‑8 assay was used to evaluate drug sensitivity. Reverse transcription‑quantitative polymerase chain reaction and western blotting were used to examine the molecular mechanisms underpinning sorafenib resistance. Migratory and invasive properties in resistant cells were assessed using Transwell assays. The results from the present study revealed that resistant cells became insensitive to sorafenib treatment and exhibited increased migratory and invasive capacities. Activation of the phosphatidylinositol‑3‑kinase (PI3K)/Akt signaling pathway and epithelial‑mesenchymal transition was characteristic of resistant cells. The use of LY294002, a PI3K inhibitor, was able to suppress the activation of Akt and extracellular signal‑regulated kinase 1/2, attenuated the migratory and invasive capacities of resistant cells. Data from the present study indicates that inhibition of the PI3K signaling pathway with LY294002 exerts suppressive effects on sorafenib resistance and provides an attractive novel therapeutic regime in patients with advanced HCC.

View Figures

View References

1	Forner A, Llovet JM and Bruix J: Hepatocellular carcinoma. Lancet. 379:1245–1255. 2012. View Article : Google Scholar : PubMed/NCBI
2	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
3	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. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
4	Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M and Carter C: Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 66:11851–11858. 2006. View Article : Google Scholar : PubMed/NCBI
5	Chen S, Wang Y, Ruan W, Wang X and Pan C: Reversing multidrug resistance in hepatocellular carcinoma cells by inhibiting extracellular signal-regulated kinase/mitogen-activated protein kinase signaling pathway activity. Oncol Lett. 8:2333–2339. 2014. View Article : Google Scholar : PubMed/NCBI
6	Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, et al: Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: A phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 10:25–34. 2009. View Article : Google Scholar : PubMed/NCBI
7	Rimassa L and Santoro A: Sorafenib therapy in advanced hepatocellular carcinoma: The SHARP trial. Expert Rev Anticancer Ther. 9:739–745. 2009. View Article : Google Scholar : PubMed/NCBI
8	Chen KF, Chen HL, Tai WT, Feng WC, Hsu CH, Chen PJ and Cheng AL: Activation of phosphatidylinositol 3-kinase/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells. J Pharmacol Exp Ther. 337:155–161. 2011. View Article : Google Scholar : PubMed/NCBI
9	Ombrato L and Malanchi I: The EMT universe: Space between cancer cell dissemination and metastasis initiation. Crit Rev Oncog. 19:349–361. 2014. View Article : Google Scholar : PubMed/NCBI
10	Wang H, Xu L, Zhu X, Wang P, Chi H and Meng Z: Activation of phosphatidylinositol 3-kinase/Akt signaling mediates sorafenib-induced invasion and metastasis in hepatocellular carcinoma. Oncol Rep. 32:1465–1472. 2014. 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	van Malenstein H, Dekervel J, Verslype C, Van Cutsem E, Windmolders P, Nevens F and van Pelt J: Long-term exposure to sorafenib of liver cancer cells induces resistance with epithelial-to-mesenchymal transition, increased invasion and risk of rebound growth. Cancer Lett. 329:74–83. 2013. View Article : Google Scholar : PubMed/NCBI
13	Chow AK, Ng L, Lam CS, Wong SK, Wan TM, Cheng NS, Yau TC, Poon RT and Pang RW: The Enhanced metastatic potential of hepatocellular carcinoma (HCC) cells with sorafenib resistance. PLoS One. 8:e786752013. View Article : Google Scholar : PubMed/NCBI
14	Mir N, Jayachandran A, Dhungel B, Shrestha R and Steel JC: Epithelial-to-mesenchymal transition: A mediator of sorafenib resistance in advanced hepatocellular carcinoma. Curr Cancer Drug Targets. 17:698–706. 2017. View Article : Google Scholar : PubMed/NCBI
15	Xu W, Yang Z and Lu N: A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition. Cell Adh Migr. 9:317–324. 2015. View Article : Google Scholar : PubMed/NCBI
16	Wen W, Ding J, Sun W, Fu J, Chen Y, Wu K, Ning B, Han T, Huang L, Chen C, et al: Cyclin G1-mediated epithelial-mesenchymal transition via phosphoinositide 3-kinase/Akt signaling facilitates liver cancer progression. Hepatology. 55:1787–1798. 2012. View Article : Google Scholar : PubMed/NCBI
17	Wu YJ, Neoh CA, Tsao CY, Su JH and Li HH: Sinulariolide suppresses human hepatocellular carcinoma cell migration and invasion by inhibiting matrix metalloproteinase-2/-9 through MAPKs and PI3K/Akt signaling pathways. Int J Mol Sci. 16:16469–16482. 2015. View Article : Google Scholar : PubMed/NCBI
18	Kunter I, Erdal E, Nart D, Yilmaz F, Karademir S, Sagol O and Atabey N: Active form of AKT controls cell proliferation and response to apoptosis in hepatocellular carcinoma. Oncol Rep. 31:573–580. 2014. View Article : Google Scholar : PubMed/NCBI
19	Dong J, Zhai B, Sun W, Hu F, Cheng H and Xu J: Activation of phosphatidylinositol 3-kinase/AKT/snail signaling pathway contributes to epithelial-mesenchymal transition-induced multi-drug resistance to sorafenib in hepatocellular carcinoma cells. PLoS One. 12:e01850882017. View Article : Google Scholar : PubMed/NCBI
20	Zhang PF, Li KS, Shen YH, Gao PT, Dong ZR, Cai JB, Zhang C, Huang XY, Tian MX, Hu ZQ, et al: Galectin-1 induces hepatocellular carcinoma EMT and sorafenib resistance by activating FAK/PI3K/AKT signaling. Cell Death Dis. 7:e22012016. View Article : Google Scholar : PubMed/NCBI
21	Xu Y, Huang J, Ma L, Shan J, Shen J, Yang Z, Liu L, Luo Y, Yao C and Qian C: MicroRNA-122 confers sorafenib resistance to hepatocellular carcinoma cells by targeting IGF-1R to regulate RAS/RAF/ERK signaling pathways. Cancer Lett. 371:171–181. 2016. View Article : Google Scholar : PubMed/NCBI
22	Chen W, Wu J, Shi H, Wang Z, Zhang G, Gao Y, Jiang C and Ding Y: Hepatic stellate cell coculture enables sorafenib resistance in Huh7 cells through HGF/c-Met/Akt and Jak2/Stat3 pathways. Biomed Res Int. 2014:7649812014.PubMed/NCBI
23	Li QL, Gu FM, Wang Z, Jiang JH, Yao LQ, Tan CJ, Huang XY, Ke AW, Dai Z, Fan J and Zhou J: Activation of PI3K/AKT and MAPK pathway through a PDGFRβ-dependent feedback loop is involved in rapamycin resistance in hepatocellular carcinoma. PLoS One. 7:e333792012. View Article : Google Scholar : PubMed/NCBI
24	Xu J, Zheng L, Chen J, Sun Y, Lin H, Jin RA, Tang M, Liang X and Cai X: Increasing AR by HIF-2α inhibitor (PT-2385) overcomes the side-effects of sorafenib by suppressing hepatocellular carcinoma invasion via alteration of pSTAT3, pAKT and pERK signals. Cell Death Dis. 8:e30952017. View Article : Google Scholar : PubMed/NCBI