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Ser‐486/491 phosphorylation and inhibition of AMPKα activity is positively associated with Gleason score, metastasis, and castration‐resistance in prostate cancer: A retrospective clinical study
Author(s) -
Babcook Melissa A.,
Akgul Mahmut,
Margevicius Seunghee,
MacLennan Gregory T.,
Fu Pingfu,
Abouassaly Robert,
Gupta Sanjay
Publication year - 2018
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.23515
Subject(s) - ampk , prostate cancer , medicine , metastasis , prostate , protein kinase a , cancer , oncology , cancer research , phosphorylation , biology , biochemistry
Background We previously demonstrated that adenosine monophosphate‐activated protein kinase (AMPKα) 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. Methods In 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‐μ sequential slides were processed for phospho‐Ser‐486/491 AMPKα 1 /α 2 , phospho‐Thr‐172 AMPKα, AMPKα 1 /α 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 AMPKα. Results Increased inhibitory Ser‐486/491 AMPKα 1 /α 2 phosphorylation, increased AMPKα protein expression, decreased AMPKα activity, and loss of nuclear AMPKα and p‐AMPKα are associated with prostate cancer progression to metastasis. Increased p‐Ser‐486/491 AMPKα 1 /α 2 was also positively correlated with higher Gleason grade and progression to castration‐resistance. Conclusions p‐Ser‐486/491 AMPKα 1 /α 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.

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