Inhibition of integrin-mediated crosstalk with epidermal growth factor receptor/Erk or Src signaling pathways in autophagic prostate epithelial cells induces caspase-independent death.
In vivo in the prostate gland, basal epithelial cells adhere to laminin 5 (LM5) via alpha3beta1 and alpha6beta4 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 alpha3beta1, but not alpha6beta4 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 alpha3beta1 and alpha6beta4, 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.
Edick
Mathew J
MJ
Laboratory of Integrin Signaling, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Tesfay
Lia
L
Lamb
Laura E
LE
Knudsen
Beatrice S
BS
Miranti
Cindy K
CK
D001343:Autophagy / Q000187:drug effects; D020169:Caspases / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D039422:Integrin alpha3 / Q000378:metabolism; D039503:Integrin alpha6 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008954:Models, Biological; D011467:Prostate / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000187:drug effects; D019061:src-Family Kinases / Q000378:metabolism*; D000097794:Kalinin
D020169:Caspases; D015815:Cell Adhesion Molecules; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D039422:Integrin alpha3; D039503:Integrin alpha6; D016023:Integrins; D008024:Ligands; D017382:Reactive Oxygen Species; D019061:src-Family Kinases; D000097794:Kalinin