Inhibition of STAT3 signaling blocks the anti-apoptotic activity of IL-6 in human liver cancer cells.
Interleukin-6 (IL-6) is a multifunctional cytokine, which may block apoptosis during inflammation to protect cells under very toxic conditions. However, IL-6 also activates STAT3 in many types of human cancer. Recent studies demonstrate that high levels of IL-6 are associated with hepatocellular carcinoma, the most common type of liver cancer. Here we reported that IL-6 promoted survival of human liver cancer cells through activating STAT3 in response to doxorubicin treatment. Endogenous IL-6 levels in SNU-449 cells were higher than in Hep3B cells. Meanwhile, SNU-449 cells were more resistant to doxorubicin than Hep3B cells. Addition of IL-6 induced STAT3 activation in Hep3B cells and led to protection against doxorubicin. In contrast, neutralizing IL-6 with anti-IL-6 antibody decreased survival of SNU-449 cells in response to doxorubicin. To elucidate the mechanism of the anti-apoptotic function of IL-6, we investigated if STAT3 mediated this drug resistance. Targeting STAT3 with STAT3 siRNA reduced the protection of IL-6 against doxorubicin-induced apoptosis, indicating that STAT3 signaling contributed to the anti-apoptotic effect of IL-6. Moreover, we further explored if a STAT3 small molecule inhibitor could abolish this anti-apoptotic effect. LLL12, a STAT3 small molecule inhibitor, blocked IL-6-induced STAT3 phosphorylation, resulting in attenuation of the anti-apoptotic activity of IL-6. Finally, neutralization of endogenous IL-6 with anti-IL-6 antibody or blockade of STAT3 with LLL12 lowered the recovery in SNU-449 cells after doxorubicin treatment. Therefore, our results demonstrated that targeting STAT3 signaling could interrupt the anti-apoptotic function of IL-6 in human liver cancer cells.
Liu
Yan
Y
Department of Pediatrics, Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43205.
Li
Pui-Kai
PK
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43205.
Li
Chenglong
C
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43205.
Lin
Jiayuh
J
Department of Pediatrics, Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43205; Experimental Therapeutics Program, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43205. Electronic address: lin.674@osu.edu.
D000880:Anthraquinones / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D000093242:Interleukin-6 Inhibitors
D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D000906:Antibodies; D004317:Doxorubicin; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D013449:Sulfonamides; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human; C549232:LLL12 compound; C494086:STAT3 protein, human