Axl receptor tyrosine kinase is up-regulated in metformin resistant prostate cancer cells

Oncotarget. 2015 Jun 20;6(17):15321-31. doi: 10.18632/oncotarget.4148.


Recent epidemiological studies showed that metformin, a widely used anti-diabetic drug might prevent certain cancers. Metformin also has an anti-proliferative effect in preclinical studies of both hematologic malignancies as well as solid cancers and clinical studies testing metformin as an anti-cancer drug are in progress. However, all cancer types do not respond to metformin with the same effectiveness or acquire resistance. To understand the mechanism of acquired resistance and possibly its mechanism of action as an anti-proliferative agent, we developed metformin resistant LNCaP prostate cancer cells. Metformin resistant LNCaP cells had an increased proliferation rate, increased migration and invasion ability as compared to the parental cells, and expressed markers of epithelial-mesenchymal transition (EMT). A detailed gene expression microarray comparing the resistant cells to the wild type cells revealed that Edil2, Ereg, Axl, Anax2, CD44 and Anax3 were the top up-regulated genes and calbindin 2 and TPTE (transmembrane phosphatase with tensin homology) and IGF1R were down regulated. We focused on Axl, a receptor tyrosine kinase that has been shown to be up regulated in several drug resistance cancers. Here, we show that the metformin resistant cell line as well as castrate resistant cell lines that over express Axl were more resistant to metformin, as well as to taxotere compared to androgen sensitive LNCaP and CWR22 cells that do not overexpress Axl. Forced overexpression of Axl in LNCaP cells decreased metformin and taxotere sensitivity and knockdown of Axl in resistant cells increased sensitivity to these drugs. Inhibition of Axl activity by R428, a small molecule Axl kinase inhibitor, sensitized metformin resistant cells that overexpressed Axl to metformin. Inhibitors of Axl may enhance tumor responses to metformin and other chemotherapy in cancers that over express Axl.

Keywords: Axl and drug resistance; Axl receptor tyrosine kinase; metformin; prostate cancer.

MeSH terms

  • Adenylate Kinase / metabolism
  • Antineoplastic Agents / pharmacology
  • Axl Receptor Tyrosine Kinase
  • Benzocycloheptenes / pharmacology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cyclin D1 / metabolism
  • Docetaxel
  • Drug Resistance, Neoplasm / physiology*
  • Enzyme Activation / drug effects
  • Epithelial-Mesenchymal Transition / physiology
  • Gene Knockdown Techniques
  • Humans
  • Male
  • Metformin / pharmacology*
  • Neoplasm Invasiveness / pathology
  • Prostatic Neoplasms / drug therapy*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / biosynthesis*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / biosynthesis*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Taxoids / pharmacology
  • Triazoles / pharmacology
  • Up-Regulation


  • Antineoplastic Agents
  • Benzocycloheptenes
  • CCND1 protein, human
  • Proto-Oncogene Proteins
  • Taxoids
  • Triazoles
  • bemcentinib
  • Cyclin D1
  • Docetaxel
  • Metformin
  • Receptor Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-akt
  • Adenylate Kinase
  • Axl Receptor Tyrosine Kinase
  • AXL protein, human