title: Activation of AKT negatively regulates the pro-apoptotic function of death-associated protein kinase 3 (DAPK3) in prostate cancer.
abstract: The activation of AKT governs many signaling pathways and promotes cell growth and inhibits apoptosis in human malignancies including prostate cancer (CaP). Here, we investigated the molecular association between AKT activation and the function of death-associated protein kinase 3 (DAPK3) in CaP. An inverse correlation of pAKT and DAPK3 expression was seen in a panel of CaP cell lines. Inhibition of AKT by wortmannin/LY294002 or overexpression of DAPK3 reverts the proliferative function of AKT in CaP cells. On the other hand, ectopic expression of AKT inhibited DAPK3 function and induced proliferation of CaP cells. In addition, AKT over-expressed tumors exhibit aggressive growth when compared to control vector in xenograft models. The immunohistochemistry results revealed a down-regulation of DAPK3 expression in AKT over-expressed tumors as compared to control tumors. Finally, we examined the expression pattern of AKT and DAPK3 in human CaP specimens - the expected gradual increase and nuclear localization of pAKT was seen in higher Gleason score samples versus benign hyperplasia (BPH). On the contrary, reduced expression of DAPK3 was seen in higher Gleason stages versus BPH. This suggests that inhibition of DAPK3 may be a contributing factor to the carcinogenesis of the prostate. Understanding the mechanism by which AKT negatively regulates DAPK3 function may suggest whether DAPK3 can be a therapeutic target for CaP.
authors.affiliation: Department of Urology, University of Louisville, Louisville, KY, USA.
authors.forename: Trinath P
authors.initials: TP
authors.lastname: Das
authors.affiliation: Department of Urology, University of Louisville, Louisville, KY, USA.
authors.forename: Suman
authors.initials: S
authors.lastname: Suman
authors.affiliation: Department of Urology, University of Louisville, Louisville, KY, USA.
authors.forename: A M Sashi
authors.initials: AM
authors.lastname: Papu John
authors.affiliation: Department of Urology, University of Louisville, Louisville, KY, USA.
authors.forename: Deeksha
authors.initials: D
authors.lastname: Pal
authors.affiliation: Department of Urology, University of Louisville, Louisville, KY, USA.
authors.forename: Angelena
authors.initials: A
authors.lastname: Edwards
authors.affiliation: Department of Pathology, University of Louisville, Louisville, KY, USA.
authors.forename: Houda
authors.initials: H
authors.lastname: Alatassi
authors.affiliation: Department of Urology, University of Louisville, Louisville, KY, USA.
authors.forename: Murali K
authors.initials: MK
authors.lastname: Ankem
authors.affiliation: Department of Urology, University of Louisville, Louisville, KY, USA. Electronic address: chendil.damodaran@louisville.edu.
authors.forename: Chendil
authors.initials: C
authors.lastname: Damodaran
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D064550:Death-Associated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D060787:Neoplasm Grading; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
chemical_list: D047428:Protein Kinase Inhibitors; C579101:DAPK3 protein, human; D064550:Death-Associated Protein Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Molecular signaling; Oncogene; Progression; Prostate cancer; Tumor suppressor