Abstract 3921: TGFβ sensitizes hepatocellular carcinoma cells to growth factors, preventing sorafenib-induced apoptosis

Abstract

Abstract Many hepatocellular carcinoma (HCC) patients have a poor prognosis due to an acquired resistance of tumors to chemotherapeutic treatment. Transforming growth factor β (TGFβ) has important roles in the control of cell differentiation, cell cycle progression, and apoptosis. An upregulation in the TGFβ signalling pathway is associated with poor prognosis in HCC patients. In this study, we aim to investigate the mechanisms by which TGFβ contributes to HCC tumor progression. We found that TGFβ significantly increases mRNA and protein levels of several mitogenic receptor tyrosine kinases, including insulin-like growth factor 1 receptor (IGF1R) and epidermal growth factor receptor (EGFR) in both time-dependent and dose-dependent manners in PLC/PRF/5 cells. Furthermore, TGFβ pretreatment significantly increases the acute cellular response to IGF1, IGF2, and EGF treatment, as measured by levels of pAKT and pERK also in both time-dependent and dose-dependent manners. We hypothesized that this increase in growth factor sensitivity would render cells resistant to sorafenib, the only approved targeted HCC chemotherapeutic agent. To test this, we pretreated PLC/PRF/5 cells with TGFβ for 48 hours then incubated the cells with sorafenib for up to 24 hours. We found that TGFβ pretreatment led to a reduction of cleaved caspases 3, 7, 9, and PARP, which are cleaved as cells undergo apoptosis. We confirmed an increase in cell viability via WST-1 assays and by counting viable cells. Lastly, we found that the TGFβRI kinase inhibitor, LY2157299, synergized with sorafenib to promote apoptosis. Taken together, our data suggests that TGFβ can enhance the survival of HCC cells by upregulating cell sensitivity to pro-survival growth factors. Furthermore, the use of both sorafenib and an inhibitor of the TGFβ signalling pathway may one day prove to be a more effective therapy for patients with advanced HCC. Citation Format: Nathan Ungerleider, Chang Han, Tong Wu. TGFβ sensitizes hepatocellular carcinoma cells to growth factors, preventing sorafenib-induced apoptosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3921. doi:10.1158/1538-7445.AM2015-3921