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Vol. 18, Issue 7, 2481-2490, July 2007

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

Mathew J. Edick^*,, Lia Tesfay^*, Laura E. Lamb^*, Beatrice S. Knudsen, and Cindy K. Miranti^*

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

Submitted April 3, 2006; Revised April 20, 2007; Accepted April 24, 2007
Monitoring Editor: Richard Assoian

In vivo in the prostate gland, basal epithelial cells adhere to laminin 5 (LM5) via 31 and 64 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 that 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 31, but not 64 integrin, supports cell survival through EGFR by signaling downstream to Erk. PC3 cells, which do not activate EGFR or Erk on LM5-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 species. In addition the presence of an autophagic pathway, maintained by adhesion to matrix through 31 and 64, 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.

Present address: Department of Physiology, Michigan State University, Lansing, MI 48824.

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

Abbreviations used: EGFR, epidermal growth factor receptor; PEC, prostate epithelial cells; LM, laminin; PI-3K, phosphatidyl inositol 3-kinase.

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