Journal Article

Aspirin enhances IFN-α-induced growth inhibition and apoptosis of hepatocellular carcinoma via JAK1/STAT1 pathway

Guo, Z-Y, Li, X-W, Chen, Z-T, Wang, C-H, Zhi, X-T, Dong, Z-R, Li, T, Tang, Z-Y, Qu, S-F

2013

Overview

STAT1 has a key role in exerting the antiproliferative and proapoptotic effects of interferon (IFN)-α on tumors, and its defects in expression is associated with IFN-α resistance. In this study we want to investigate whether aspirin can improve the antitumor efficiency of IFN-α on hepatocellular carcinoma (HCC) through the activation of STAT1. We found that aspirin not only significantly enhanced IFN-α-induced antiproliferation and apoptosis of HCC in vitro study but also enhanced tumor growth inhibition in nude mice. Although IFN-α alone resulted in significant phosphorylation of both STAT1 and STAT3, aspirin only prompted the IFN-α-induced phosphorylation of STAT1. Further study revealed that aspirin-prompted phosphorylation of STAT1 was activated through phosphorylation of JAK1. Furthermore, aspirin-activated STAT1 upregulated the transcription of proapoptotic IFN-stimulated gene (ISG) of X-linked inhibitor of apoptosis-associated factor-1 and downregulated the transcription of antiapoptotic ISG of G1P3, which in turn promoted the expression of Bax and activation of caspase-9 and caspase-3, thereby sensitizing HCC cells to IFN-α-induced apoptosis. Taken together, our findings suggest a novel strategy of using aspirin to overcome tumor resistance and enhance the effectiveness of IFN-α in HCC treatment through activating STAT1 gene, and have potential implications for improving future IFN-α protein and gene therapy.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/154/51/201 / 631/67/1059/99 / 631/67/1504/1610 / 631/80/86 / Animals / Apoptosis / Apoptosis - drug effects / Aspirin / Aspirin - administration & dosage / Bax protein / Biomedical and Life Sciences / Biomedicine / Cancer / Carcinoma, Hepatocellular - drug therapy / Carcinoma, Hepatocellular - metabolism / Carcinoma, Hepatocellular - pathology / Care and treatment / Caspase-3 / Caspase-9 / Cell Proliferation - drug effects / Dosage and administration / Drug Resistance, Neoplasm - drug effects / Drug Synergism / Drug therapy / Gene Expression / Gene Expression Regulation, Neoplastic - drug effects / Gene Therapy / Genetic aspects / Growth inhibition / Hepatocellular carcinoma / Hepatoma / Humans / Interferon / Interferon-alpha - administration & dosage / Interferon-alpha - metabolism / Janus kinase / Janus Kinase 1 - biosynthesis / Liver cancer / Liver Neoplasms - drug therapy / Liver Neoplasms - metabolism / Liver Neoplasms - pathology / Methods / Mice / original-article / Patient outcomes / Phosphorylation / Signal Transduction / Stat1 protein / STAT1 Transcription Factor - biosynthesis / Stat3 protein / Transcription / Tumors / α-Interferon