Abstract 4016: Rapamycin-resistant HIF-1α expression in hepatocellular carcinoma (HCC) cells and high sensitivity of endothelial cells within HCC tissues to rapamycin.

Abstract

Abstract HIF-1 plays a pivotal role in cancer development via cellular growth,proliferation, survival, metabolism and angiogenesis. High expression of HIF-1α, a regulatory component of HIF-1, in cancer cells is due to increased synthesis of HIF-1α via the increased translation of HIF-1α mRNA under the influence of activated mTORC1 signaling as well as decreased HIF-1α degradation that is either on oxygen-dependent or independent mechanism. In mouse hepatocarcinogenesis, our previous data demonstrated that HIF-1α is overexpressed depending on the PI3K-Akt pathway from earliest stage and that HIF-1α knockdown by using siRNA resulted in marked growth retardation and cell death in HCC cells. We here demonstrated that Akt, 4E binding protein 1 (4EBP1) and p70 ribosomal protein S6 kinase (S6K) were hyperphosphorylated in mouse hepatic tumors and HCC cells, indicating that the PI3K-Akt-mTORC1 pathway was activated. However, although rapamycin, an inhibitor of mTORC1, effectively suppressed phosphorylation of 4EBP1 and S6K in HCC cells, HCC cells were resistant to rapamycin where HIF-1α continued to be expressed during rapamycin treatment. This HIF-1α expression was due to de novo synthesis of HIF-1α during rapamycin treatment as well as HIF-1α stabilization due to binding of HIF-1α to HSP90 that was constitutively over-expressed in the HCC cells. On the other hand, rapamycin induced extensive hemorrhagic necrosis in HCC tissues in vivo but not in normal liver or adenomas (benign lesions). Phosphorylated ribosome protein subunit 6 (rps6), the downstream phosphorylation target of mTORC1-S6K pathway, was specifically detected in the endothelial cells within HCCs but not those in normal liver or adenomas. Furthermore, rapamycin decreased proliferation of endothelial cells in vitro, reducing HIF-1α expression together with the decreased 4EBP and S6K phosphorylation, indicating that the endothelial cells within HCCs were especially sensitive to rapamycin. Dual treatment with inhibitors for mTOR and HSP90, therefore, could target both HCC cells and endothelial cells within HCCs, which might be an effective therapy for HCCs. Citation Format: Hiroki Tanaka, Masahiro Yamamoto, Masaaki Miyakoshi, Katsuhiro Ogawa. Rapamycin-resistant HIF-1α expression in hepatocellular carcinoma (HCC) cells and high sensitivity of endothelial cells within HCC tissues to rapamycin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4016. doi:10.1158/1538-7445.AM2013-4016