Diverse antiapoptotic signaling pathways activated by vasoactive intestinal polypeptide, epidermal growth factor, and phosphatidylinositol 3-kinase in prostate cancer cells converge on BAD.
It has been demonstrated that vasoactive intestinal polypeptide, epidermal growth factor, and chronic activation of phosphatidylinositol 3-kinase can protect prostate cancer cells from apoptosis; however, the signaling pathways that they use and molecules that they target are unknown. We report that vasoactive intestinal polypeptide, epidermal growth factor, and phosphatidylinositol 3-kinase activate independent signaling pathways that phosphorylate the proapoptotic protein BAD. Vasoactive intestinal polypeptide operated via protein kinase A, epidermal growth factor required Ras activity, and effects of phosphatidylinositol 3-kinase were predominantly mediated by Akt. BAD phosphorylation was critical for the antiapoptotic effects of each signaling pathway. None of these survival signals was able to rescue cells that express BAD with mutations in phosphorylation sites, whereas knockdown of BAD expression with small hairpin RNA rendered cells insensitive to apoptosis. Taken together, these results identify BAD as a convergence point of several antiapoptotic signaling pathways in prostate cells.
Sastry
Konduru S R
KSR
Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157.
Smith
Adrienne Joy
AJ
Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157.
Karpova
Yelena
Y
Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157.
Datta
Sandeep Robert
SR
Center for Neurobiology and Behavior, Columbia University, New York, New York 10032.
Kulik
George
G
Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157. Electronic address: gkulik@wfubmc.edu.
D017209:Apoptosis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction; D014660:Vasoactive Intestinal Peptide / Q000737:chemistry*; D051025:bcl-Associated Death Protein / Q000378:metabolism / Q000502:physiology*
D051025:bcl-Associated Death Protein; D014660:Vasoactive Intestinal Peptide; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D017868:Cyclic AMP-Dependent Protein Kinases