Autophagy blockade sensitizes prostate cancer cells towards src family kinase inhibitors

Zhaoju Wu, Pei Ching Chang, Joy C. Yang, Cheng Ying Chu, Ling Yu Wang, Nien Tsu Chen, Ai Hong Ma, Sonal J. Desai, Su Hao Lo, Christopher P. Evans, Kit S Lam, Hsing Jien Kung

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

There is overwhelming evidence that tyrosine kinases play an important role in cancer development. As a prototype of targeted therapy, tyrosine kinase inhibitors are now successfully applied to cancer treatment. However, as single agents, tyrosine kinase inhibitors have not achieved satisfactory results in the treatment of prostate cancer, principally due to their inability to efficiently kill tumor cells. The authors' laboratory has been interested in the role of the Src complex in prostate cancer progression, including the induction of androgen independence and metastasis. Previously, the authors reported that Src inhibitors such as saracatinib and PP2 caused G1 growth arrest and diminished invasiveness in prostate cancer cells but rarely apoptosis. Here, they have shown that Src family kinase (SFK) inhibitors can induce a high level of autophagy, which protects treated cells from undergoing apoptosis. Src siRNA knockdown experiments confirmed that autophagy was indeed caused by the lack of Src activity. The SFK inhibitor-induced autophagy is accompanied by the inhibition of the PI3K (type I)/Akt/mTOR signaling pathway. To test whether autophagy blockade could lead to enhanced cell death, pharmacological inhibitors (3-methyladenine and chloroquine) and a genetic inhibitor (siRNA targeting Atg7) were used in combination with SFK inhibitors. The results showed that autophagy inhibition effectively enhanced cell killing induced by SFK inhibitors. Importantly, the authors showed that a combination of saracatinib with chloroquine in mice significantly reduced prostate cancer (PC3) xenograft growth compared with the control group. Taken together, these data suggest that (1) autophagy serves a protective role in SFK inhibitor-mediated cell killing, and (2) clinically acceptable autophagy modulators may be used beneficially as adjunctive therapeutic agents for SFK inhibitors.

Original languageEnglish
Pages (from-to)40-49
Number of pages10
JournalGenes and Cancer
Volume1
Issue number1
DOIs
Publication statusPublished - 2010
Externally publishedYes

Keywords

  • Autophagy
  • Chloroquine
  • Prostate cancer
  • Saracatinib
  • Src tyrosine kinase

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

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  • Cite this

    Wu, Z., Chang, P. C., Yang, J. C., Chu, C. Y., Wang, L. Y., Chen, N. T., Ma, A. H., Desai, S. J., Lo, S. H., Evans, C. P., Lam, K. S., & Kung, H. J. (2010). Autophagy blockade sensitizes prostate cancer cells towards src family kinase inhibitors. Genes and Cancer, 1(1), 40-49. https://doi.org/10.1177/1947601909358324