title: Activation of PI3K/AKT and MAPK pathway through a PDGFRβ-dependent feedback loop is involved in rapamycin resistance in hepatocellular carcinoma.
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.
  
  
  RESULTS
  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.
authors.affiliation: Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, People's Republic of China.
authors.forename: Quan-Lin
authors.initials: QL
authors.lastname: Li
authors.forename: Fang-Ming
authors.initials: FM
authors.lastname: Gu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Jia-Hao
authors.initials: JH
authors.lastname: Jiang
authors.forename: Li-Qing
authors.initials: LQ
authors.lastname: Yao
authors.forename: Chang-Jun
authors.initials: CJ
authors.lastname: Tan
authors.forename: Xiao-Yong
authors.initials: XY
authors.lastname: Huang
authors.forename: Ai-Wu
authors.initials: AW
authors.lastname: Ke
authors.forename: Zhi
authors.initials: Z
authors.lastname: Dai
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D025461:Feedback, Physiological / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology*; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D034741:RNA, Small Interfering; D013778:Tetrazolium Salts; D013844:Thiazoles; D019869:Phosphatidylinositol 3-Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; C022616:thiazolyl blue; D020123:Sirolimus