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

PLoS One. 2012;7(3):e33379. doi: 10.1371/journal.pone.0033379. Epub 2012 Mar 9.


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 PDGFRβ in a time and dose-dependent manner as assessed by RT-PCR and western blot analysis. Using siRNA mediated knockdown of PDGFRβ, we confirmed that subsequent activation of AKT and ERK was PDGFRβ-dependent and compromised the anti-tumor activity of rapamycin. Then, blockade of this PDGFRβ-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / physiology*
  • Enzyme Activation / physiology
  • Feedback, Physiological / physiology*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Gene Silencing
  • Humans
  • Immunohistochemistry
  • Liver Neoplasms / metabolism*
  • Male
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering / genetics
  • Rats
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • Sirolimus / pharmacology*
  • Tetrazolium Salts
  • Thiazoles


  • RNA, Small Interfering
  • Tetrazolium Salts
  • Thiazoles
  • Phosphatidylinositol 3-Kinases
  • Receptor, Platelet-Derived Growth Factor beta
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • thiazolyl blue
  • Sirolimus