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MBC in Press, published online ahead of print May 2, 2007
Mol. Biol. Cell 10.1091/mbc.E06-04-0261

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Submitted on April 3, 2006
Revised on April 20, 2007
Accepted on April 24, 2007

Inhibition of Integrin-mediated Crosstalk with EGFR/Erk or Src Signaling Pathways in Autophagic Prostate Epithelial Cells Induces Caspase-independent Death

Mathew J. Edick,*{dagger} Lia Tesfay,* Laura E. Lamb,* Beatrice S. Knudsen,{ddagger} and Cindy K. Miranti*

*Laboratory of Integrin Signaling, Van Andel Research Institute, Grand Rapids, MI 49503; {ddagger}Division of Public Health Sciences, Program in Cancer Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109

Monitoring Editor: Richard Assoian

In vivo in the prostate gland, basal epithelial cells adhere to laminin 5 (LM5) via {alpha}3{beta}1 and {alpha}6{beta}4 integrins. When placed in culture primary prostate basal epithelial cells secrete and adhere to their own LM5-rich matrix. Adhesion to LM5 is required for cell survival which is dependent on integrin-mediated, ligand-independent activation of the epidermal growth factor receptor (EGFR) and the cytoplasmic tyrosine kinase Src, but not PI-3K. Integrin-mediated adhesion via {alpha}3{beta}1, but not {alpha}6{beta}4 integrin, supports cell survival through EGFR by signaling downstream to Erk. PC3 cells, which do not activate EGFR or Erk on laminin 5-rich matrices, are not dependent on this pathway for survival. PC3 cells are dependent on PI-3K for survival and undergo caspase-dependent death when PI-3K is inhibited. The death induced by inhibition of EGFR or Src in normal primary prostate cells is not mediated through or dependent on caspase activation, but depends on the induction of reactive oxygen. In addition the presence of an autophagic pathway, maintained by adhesion to matrix through {alpha}3{beta}1 and {alpha}6{beta}4, prevents the induction of caspases when EGFR or Src is inhibited. Suppression of autophagy is sufficient to induce caspase activation and apoptosis in LM5-adherent primary prostate epithelial cells.

{dagger}Present address: Department of Physiology, Michigan State University, Lansing, MI.

Address correspondence to: Cindy K. Miranti (cindy.miranti{at}vai.org)




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