Journal Article
Ser-486/491 phosphorylation and inhibition of AMPK activity is positively associated with Gleason score, metastasis, and castration-resistance in prostate cancer: A retrospective clinical study
Abouassaly, R; Akgul, M; Babcook, MA; Fu, PF; Gupta, S; Maclennan, GT; Margevicius, S
Prostate
ISSN: 0270-4137
EISSN: 1097-0045
BackgroundWe previously demonstrated that adenosine monophosphate-activated protein kinase (AMPK) activity is significantly inhibited by Ser-486/491 phosphorylation in cell culture and in vivo models of metastatic and castration-resistant prostate cancer, and hypothesized these findings may translate to clinical specimens. MethodsIn this retrospective, single-institution pilot study, 45 metastatic prostate cancer cases were identified within the University Hospitals Cleveland Medical Center Pathology Archive with both metastasis and matched primary prostate tumor specimens in formalin-fixed, paraffin-embedded blocks, and complete electronic medical records. Thirty non-metastatic, hormone-dependent prostate cancer controls, who were progression-free as defined by undetectable prostate specific antigen for at least 79.6 months (range 79.6-136.0 months), and matched metastatic cases based on age, race, and year of diagnosis. All specimens were collected from 1991 to 2014; primary tumor specimens were obtained via diagnostic biopsy or prostatectomy, and metastasis specimens obtained via surgery or perimortem. 5- sequential slides were processed for phospho-Ser-486/491 AMPK(1)/(2), phospho-Thr-172 AMPK, AMPK(1)/(2), phospho-Ser-792 Raptor, phospho-Ser-79 acetyl-CoA carboxylase, and phospho-Ser-872, 3-hydroxy-3-methylglutaryl-CoA reductase immunohistochemistry to determine expression, phosphorylation pattern, and activity of AMPK. ResultsIncreased inhibitory Ser-486/491 AMPK(1)/(2) phosphorylation, increased AMPK protein expression, decreased AMPK activity, and loss of nuclear AMPK and p-AMPK are associated with prostate cancer progression to metastasis. Increased p-Ser-486/491 AMPK(1)/(2) was also positively correlated with higher Gleason grade and progression to castration-resistance. Conclusionsp-Ser-486/491 AMPK(1)/(2) is a novel marker of prostate cancer metastasis and castration-resistance. Ser-486/491 phosphokinases should be pursued as targets for metastatic and castration-resistant prostate cancer chemotherapy.
AMP-activated protein kinase, castration-resistant prostate cancer,; clinical specimens, metastasis, pathology, prostatic neoplasms; FAMILY-HISTORY, CELLS, RISK, ACTIVATOR, THERAPY, KINASE, ENERGY, GRADE