Activation of PI3K/AKT and MAPK pathway through a PDGFR?-dependent feedback loop is involved in rapamycin resistance in hepatocellular carcinoma.

ABSTRACT: Rapamycin is an attractive approach for the treatment and prevention of HCC recurrence after liver transplantation. However, the objective response rates of rapamycin achieved with single-agent therapy were modest, supporting that rapamycin resistance is a frequently observed characteristic of many cancers. Some studies have been devoted to understanding the mechanisms of rapamycin resistance, however, the mechanisms are cell-type-dependent and studies on rapamycin resistance in HCC are extremely limited.The anti-tumor sensitivity of rapamycin was modest in vitro and in vivo. In both human and rat HCC cells, rapamycin up-regulated the expression and phosphorylation of PDGFR? in a time and dose-dependent manner as assessed by RT-PCR and western blot analysis. Using siRNA mediated knockdown of PDGFR?, we confirmed that subsequent activation of AKT and ERK was PDGFR?-dependent and compromised the anti-tumor activity of rapamycin. Then, blockade of this PDGFR?-dependent feedback loop by sorafenib enhanced the anti-tumor sensitivity of rapamycin in vitro and in an immunocompetent orthotopic rat model of HCC.Activation of PI3K/AKT and MAPK pathway through a PDGFR?-dependent feedback loop compromises the anti-tumor activity of rapamycin in HCC, and blockade of this feedback loop by sorafenib is an attractive approach to improve the anti-tumor effect of rapamycin, particularly in preventing or treating HCC recurrence after liver transplantation.

SUBMITTER: Li QL 

PROVIDER: S-EPMC3302853 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature