TGFβ Signaling Confers Sorafenib Resistance via Induction of Multiple RTKs in Hepatocellular Carcinoma Cells

Transforming growth factor beta (TGF beta) is a multifunctional cytokine which is importantly implicated in hepatocarcinogenesis. The current study provides novel evidence that TGF beta upregulates the expression of multiple receptor tyrosine kinases (RTKs), including IGF1R, EGFR, PDGF beta R, 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 TGF beta-mediated increase in growth factor sensitivity led to evasion of apoptosis induced by the mutikinase inhibitor, sorafenib. Conversely, we observed that inhibition of the TGF beta signaling pathway by LY2157299, a TGF beta RI kinase inhibitor, enhanced sorafenibinduced apoptosis, in vitro. Our findings disclose an important interplay between TGF beta and RTK signaling pathways, which is critical for hepatocellular cancer cell survival and resistance to therapy. (C) 2016 Wiley Periodicals, Inc.