The Receptor Tyrosine Kinase Axl Is an Essential Regulator of Prostate Cancer Proliferation and Tumor Growth and Represents a New Therapeutic Target

Oncogene. 2013 Feb 7;32(6):689-98. doi: 10.1038/onc.2012.89. Epub 2012 Mar 12.

Abstract

Deregulation of the receptor tyrosine kinase Axl has been implicated in the progression of several human cancers. However, the role of Axl in prostate cancer remains poorly understood, and the therapeutic efficacy of Axl targeting remains untested. In this report we identified Axl as a new therapeutic target for prostate cancer. Axl is consistently overexpressed in prostate cancer cell lines and human prostate tumors. Interestingly, the blockage of Axl gene expression strongly inhibits proliferation, migration, invasion and tumor growth. Furthermore, inhibition of Axl expression by small interfering RNA regulates a transcriptional program of genes involved in cell survival, strikingly all connected to the nuclear factor-κB pathway. Additionally, blockage of Axl expression leads to inhibition of Akt, IKKα and IκBα phosphorylation, increasing IκBα expression and stability. Furthermore, induction of Akt phosphorylation by insulin-like growth factor 1 in Axl knockdown cells restores Akt activity and proliferation. Taken together, our results establish an unambiguous role for Axl in prostate cancer tumorigenesis with implications for prostate cancer treatment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Transformation, Neoplastic*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Molecular Targeted Therapy
  • NF-kappa B / metabolism
  • Neoplasm Metastasis
  • Prostatic Neoplasms / genetics*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Signal Transduction
  • Up-Regulation

Substances

  • NF-kappa B
  • Proto-Oncogene Proteins
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase