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.

Abstract

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 AMPKα1 /α2 , phospho-Thr-172 AMPKα, AMPKα1 /α2 , 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 AMPKα1 /α2 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 AMPKα1 /α2 was also positively correlated with higher Gleason grade and progression to castration-resistance.

CONCLUSIONS:

p-Ser-486/491 AMPKα1 /α2 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.

• Authors: Melissa A Babcook, Mahmut Akgul, Seunghee Margevicius, Gregory T MacLennan, Pingfu Fu, Robert Abouassaly, Sanjay Gupta
• Journal: The Prostate (Prostate) Vol. 78 Issue 10 Pg. 714-723 (07 2018) ISSN: 1097-0045 [Electronic] United States
• PMID: 29577356 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2018 Wiley Periodicals, Inc.

Chemical References

• Biomarkers, Tumor
• EIF3A protein, human
• Eukaryotic Initiation Factor-3
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Aged
• Biomarkers, Tumor
• Eukaryotic Initiation Factor-3 (antagonists & inhibitors, metabolism)
• Humans
• Male
• Middle Aged
• Neoplasm Metastasis
• Phosphorylation
• Pilot Projects
• Prostatic Neoplasms, Castration-Resistant (metabolism, pathology)
• Retrospective Studies