1. Activation of PI3K/AKT and MAPK Pathway through a PDGFRβ-Dependent Feedback Loop Is Involved in Rapamycin Resistance in Hepatocellular Carcinoma.
- Author
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Quan-Lin Li, Fang-Ming Gu, Zheng Wang, Jia-Hao Jiang, Li-Qing Yao, Chang-Jun Tan, Xiao-Yong Huang, Ai-Wu Ke, Zhi Dai, Jia Fan, and Jian Zhou
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RAPAMYCIN , *LIVER transplantation , *WESTERN immunoblotting , *TUMORS , *PHOSPHORYLATION , *CANCER - Abstract
Background: 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. Methodology/Principal Findings: 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 PDGFRb in a time and dose-dependent manner as assessed by RT-PCR and western blot analysis. Using siRNA mediated knockdown of PDGFRb, we confirmed that subsequent activation of AKT and ERK was PDGFRb-dependent and compromised the anti-tumor activity of rapamycin. Then, blockade of this PDGFRb-dependent feedback loop by sorafenib enhanced the anti-tumor sensitivity of rapamycin in vitro and in an immunocompetent orthotopic rat model of HCC. Conclusions: Activation of PI3K/AKT and MAPK pathway through a PDGFRβ-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. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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