Dasatinib induces autophagic cell death in human ovarian cancer

Cancer. 2010 Nov 1;116(21):4980-90. doi: 10.1002/cncr.25426.

Abstract

Background: Dasatinib, an inhibitor of Src/Abl family kinases, can inhibit tumor growth of several solid tumors. However, the effect and mechanism of action of dasatinib in human ovarian cancer cells remains unknown.

Methods: Dasatinib-induced autophagy was determined by acridine orange staining, punctate localization of GFP-LC3, LC3 protein blotting, and electron microscopy. Significance of beclin 1, AKT, and Bcl-2 in dasatinib-induced autophagy and growth inhibition was assayed by small interfering RNA (siRNA) silencing and/or overexpression of the gene of interest.

Results: Dasatinib inhibited cell growth by inducing little apoptosis, but substantial autophagy in SKOv3 and HEY ovarian cancer cells. In vivo studies showed dasatinib inhibited tumor growth and induced both autophagy and apoptosis in a HEY xenograft model. Knockdown of beclin 1 and Atg12 expression with their respective siRNAs diminished dasatinib-induced autophagy, whereas knockdown of p27Kip1 with specific siRNAs did not. Small hairpin RNA knockdown of beclin 1 expression reduced dasatinib-induced autophagy and growth inhibition. Dasatinib reduced the phosphorylation of AKT, mTOR, p70S6K, and S6 kinase expression. Constitutive expression of AKT1 and AKT2 inhibited dasatinib-induced autophagy in both HEY and SKOv3 cells. Dasatinib also reduced Bcl-2 expression and activity. Overexpression of Bcl-2 partially prevented dasatinib-induced autophagy.

Conclusions: Dasatinib induces autophagic cell death in ovarian cancer that partially depends on beclin 1, AKT, and Bcl-2. These results may have implications for clinical use of dasatinib.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy / drug effects*
  • Autophagy-Related Protein 12
  • Beclin-1
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dasatinib
  • Female
  • Humans
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Nude
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / pathology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • Small Ubiquitin-Related Modifier Proteins / metabolism
  • Thiazoles / pharmacology*
  • Thiazoles / therapeutic use
  • Xenograft Model Antitumor Assays

Substances

  • ATG12 protein, human
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Autophagy-Related Protein 12
  • BECN1 protein, human
  • Beclin-1
  • HRK protein, human
  • Membrane Proteins
  • Pyrimidines
  • Small Ubiquitin-Related Modifier Proteins
  • Thiazoles
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-akt
  • Dasatinib