title: Aspirin enhances IFN-α-induced growth inhibition and apoptosis of hepatocellular carcinoma via JAK1/STAT1 pathway.
abstract: 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.
authors.affiliation: Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: T
authors.initials: T
authors.lastname: Li
authors.forename: Z-R
authors.initials: ZR
authors.lastname: Dong
authors.forename: Z-Y
authors.initials: ZY
authors.lastname: Guo
authors.forename: C-H
authors.initials: CH
authors.lastname: Wang
authors.forename: Z-Y
authors.initials: ZY
authors.lastname: Tang
authors.forename: S-F
authors.initials: SF
authors.lastname: Qu
authors.forename: Z-T
authors.initials: ZT
authors.lastname: Chen
authors.forename: X-W
authors.initials: XW
authors.lastname: Li
authors.forename: X-T
authors.initials: XT
authors.lastname: Zhi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000008:administration & dosage*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000378:metabolism; D053613:Janus Kinase 1 / Q000096:biosynthesis*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D050794:STAT1 Transcription Factor / Q000096:biosynthesis*; D015398:Signal Transduction
chemical_list: D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D001241:Aspirin