title: BAD dephosphorylation and decreased expression of MCL-1 induce rapid apoptosis in prostate cancer cells.
abstract: PTEN loss and constitutive activation of the PI3K signaling pathway have been associated with advanced androgen-independent prostate cancer. PTEN-deficient prostate cancer C42Luc cells survive in serum-free media and show relative resistance to apoptosis even in the presence of the PI3K inhibitor ZSTK474. Yet, when ZSTK474 is combined with the translation inhibitor cycloheximide, C42Luc cells undergo apoptosis within 6 hours. We identified dephosphorylation of BAD (Bcl2-associated death promoter) as a main apoptosis-regulatory molecule downstream from PI3K, and loss of MCL-1 (Myeloid cell leukemia -1) as a major target of cycloheximide. The combination of MCL-1 knockdown and expression of phosphorylation-deficient mutant BAD2SA is sufficient to trigger rapid apoptosis in prostate cancer cells. These results establish the mechanism for the synergistic induction of apoptosis by the combination of a PI3K inhibitor and of a protein synthesis inhibitor in PTEN-deficient prostate cancer cells.
authors.affiliation: Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Dana
authors.initials: D
authors.lastname: Yancey
authors.forename: Kyle C
authors.initials: KC
authors.lastname: Nelson
authors.forename: Daniele
authors.initials: D
authors.lastname: Baiz
authors.forename: Sazzad
authors.initials: S
authors.lastname: Hassan
authors.forename: Anabel
authors.initials: A
authors.lastname: Flores
authors.forename: Ashok
authors.initials: A
authors.lastname: Pullikuth
authors.forename: Yelena
authors.initials: Y
authors.lastname: Karpova
authors.forename: Linara
authors.initials: L
authors.lastname: Axanova
authors.forename: Victoria
authors.initials: V
authors.lastname: Moore
authors.forename: Guangchao
authors.initials: G
authors.lastname: Sui
authors.forename: George
authors.initials: G
authors.lastname: Kulik
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D016895:Culture Media, Serum-Free / Q000737:chemistry; D003513:Cycloheximide / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D014227:Triazines / Q000494:pharmacology; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D016895:Culture Media, Serum-Free; D003513:Cycloheximide; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors; D014227:Triazines; D051025:bcl-Associated Death Protein; C494819:BAD protein, human; C579095:MCL1 protein, human; C510150:ZSTK474; C494929:PTEN protein, human
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