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TGFβ signaling confers sorafenib resistance via induction of multiple RTKs in hepatocellular carcinoma cells
Author(s) -
Ungerleider Nathan,
Han Chang,
Zhang Jinqiang,
Yao Lu,
Wu Tong
Publication year - 2017
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22592
Subject(s) - sorafenib , biology , receptor tyrosine kinase , cancer research , hepatocellular carcinoma , transforming growth factor , signal transduction , platelet derived growth factor receptor , cytokine , apoptosis , tyrosine kinase , transforming growth factor beta , growth factor , receptor , microbiology and biotechnology , immunology , biochemistry
Transforming growth factor β (TGFβ) is a multifunctional cytokine which is importantly implicated in hepatocarcinogenesis. The current study provides novel evidence that TGFβ upregulates the expression of multiple receptor tyrosine kinases (RTKs), including IGF1R, EGFR, PDGFβR, and FGFR1 in human hepatocellular carcinoma (HCC) cells. This, in turn, sensitized HCC cells to individual cognate RTK ligands, leading to cell survival. Our data showed that the TGFβ‐mediated increase in growth factor sensitivity led to evasion of apoptosis induced by the mutikinase inhibitor, sorafenib. Conversely, we observed that inhibition of the TGFβ signaling pathway by LY2157299, a TGFβRI kinase inhibitor, enhanced sorafenib‐induced apoptosis, in vitro. Our findings disclose an important interplay between TGFβ and RTK signaling pathways, which is critical for hepatocellular cancer cell survival and resistance to therapy. © 2016 Wiley Periodicals, Inc.