title: Epidermal growth factor protects prostate cancer cells from apoptosis by inducing BAD phosphorylation via redundant signaling pathways.
abstract: Protection from apoptosis by receptor tyrosine kinases, resistant to the inhibition of phosphatidylinositol 3 '-kinase/Akt and Ras/MEK pathways, has been reported in several cell types, including fibroblasts and epithelial prostate cancer cells; however, mechanisms of this effect were not clear. Here we report that in prostate cancer cells, epidermal growth factor activates two antiapoptotic signaling pathways that impinge on the proapoptotic protein BAD. One signaling cascade operates via the Ras/MEK module and induces BAD phosphorylation on Ser112. Another pathway predominantly relies on Rac/PAK1 signaling that leads to BAD phosphorylation on Ser136. Each of these two pathways is sufficient to protect cells from apoptosis, and therefore both have to be inhibited simultaneously to block epidermal growth factor-dependent survival. Redundancy of antiapoptotic signaling pathways should be considered when therapies targeting antiapoptotic mechanisms are designed.
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
authors.forename: Konduru S R
authors.initials: KS
authors.lastname: Sastry
authors.forename: Yelena
authors.initials: Y
authors.lastname: Karpova
authors.forename: George
authors.initials: G
authors.lastname: Kulik
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008954:Models, Biological; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D015398:Signal Transduction; D051025:bcl-Associated Death Protein / Q000378:metabolism*
chemical_list: D051025:bcl-Associated Death Protein; D004815:Epidermal Growth Factor; D019908:Proto-Oncogene Proteins c-raf