Sorafenib overcomes TRAIL resistance of hepatocellular carcinoma cells through the inhibition of STAT3.
OBJECTIVE
Recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising antitumor agent. However, many hepatocellular carcinoma (HCC) cells show resistance to TRAIL-induced apoptosis. Here, we report that sorafenib improves the antitumor effect of TRAIL-related agents in resistant HCC.


METHODS
HCC cell lines (PLC5, Huh-7, Hep3B, and Sk-Hep1) were treated with sorafenib and/or TRAIL-related agents (TRAIL or LBY135) and analyzed in terms of apoptosis and signal transduction. In vivo efficacy was determined in nude mice with PLC5 xenografts.


RESULTS
Sorafenib, the only approved drug for HCC, sensitizes resistant HCC cells to an agonistic DR5 antibody (LBY135) and TRAIL-induced apoptosis in TRAIL-resistant HCC cells. We found that STAT3 played a significant role in mediating TRAIL sensitization. Our data showed that sorafenib downregulated phospho-STAT3 (pSTAT3) and subsequently reduced the expression levels of STAT3-related proteins (Mcl-1, survivin, and cyclin D1) in a dose- and time-dependent manner in TRAIL-treated HCC cells. Knockdown of STAT3 by RNA interference overcame apoptotic resistance to TRAIL in HCC cells, and ectopic expression of STAT3 in HCC cells abolished the TRAIL-sensitizing effect of sorafenib. Moreover, SHP-1 inhibitor reversed downregulation of pSTAT3 and apoptosis induced by sorafenib, and silencing of SHP-1 by RNA interference abolished the effects of sorafenib on pSTAT3. Notably, sorafenib increased SHP-1 activity in PLC5 cells. Finally, sorafenib plus LBY135 significantly suppressed PLC5 xenograft tumor growth.


CONCLUSIONS
Sorafenib sensitizes resistant HCC cells to TRAIL-induced apoptosis at clinical achievable concentrations, and this effect is mediated via the inhibition of STAT3.
Chen
Kuen-Feng
KF
Department of Medical Research, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Tai
Wei-Tien
WT
Liu
Tsung-Hao
TH
Huang
Hsiang-Po
HP
Lin
Yu-Chin
YC
Shiau
Chung-Wai
CW
Li
Pui-Kai
PK
Chen
Pei-Jer
PJ
Cheng
Ann-Lii
AL
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010766:Phosphorylation / Q000187:drug effects; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D053221:TNF-Related Apoptosis-Inducing Ligand; D009536:Niacinamide; D000077157:Sorafenib; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse