Overexpression of Yes-associated protein confers doxorubicin resistance in hepatocellullar carcinoma

Oncol Rep. 2013 Feb;29(2):840-6. doi: 10.3892/or.2012.2176. Epub 2012 Dec 10.

Abstract

Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies worldwide and is highly resistant to chemotherapy. Yes-associated protein (YAP) is the downstream effector of the Hippo signaling pathway, which is frequently overexpressed in many types of cancers. Amplification of the YAP gene and overexpression of YAP in HCC have previously been reported to contribute to hepatocyte malignant transformation and tumor progression. In this study, we aimed to investigate the potential role of YAP in HCC chemoresistance. Overexpression of YAP resulted in resistance against doxorubicin-induced apoptosis in HCC cell lines, whereas suppression of the endogenous YAP expression by RNA interference demonstrated the reverse effect. Western blotting revealed that, following exposure to doxorubicin, YAP-overexpressing cells exhibited decreased cleaved PARP, increased phosphorylation of Akt and ERK1/2, and elevated Bcl-xL expression in comparison to the vector control. Inhibition of YAP expression sensitized HCC cells to doxorubicin, by exhibiting increased cleaved PARP, decreased levels of phosphorylated Akt, phosphorylated ERK1/2 and Bcl-xL expression. In addition, pretreatment with the MEK1/2 inhibitor U0126 but not the PI3-K inhibitor LY294002 significantly enhanced doxorubicin-induced apoptosis and decreased Bcl-xL expression in YAP-overexpressing HCC cells. Our data provide evidence that overexpression of YAP plays an important role in conferring doxorubicin resistance to HCC, which is at least partially mediated by YAP-induced activation of the MAP kinase pathway. Targeting YAP may be a promising adjunct for overcoming doxorubicin resistance in HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Antibiotics, Antineoplastic / pharmacology*
  • Apoptosis / drug effects
  • Butadienes / pharmacology
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Line, Tumor
  • Chromones / pharmacology
  • Doxorubicin / pharmacology*
  • Drug Resistance, Neoplasm*
  • Humans
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / metabolism*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Morpholines / pharmacology
  • Nitriles / pharmacology
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation / drug effects
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Signal Transduction
  • Transcription Factors
  • bcl-X Protein / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Antibiotics, Antineoplastic
  • BCL2L1 protein, human
  • Butadienes
  • Chromones
  • Morpholines
  • Nitriles
  • Phosphoproteins
  • Transcription Factors
  • U 0126
  • YAP1 protein, human
  • bcl-X Protein
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Doxorubicin
  • Poly(ADP-ribose) Polymerases
  • Proto-Oncogene Proteins c-akt
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3