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

Prostate. 2018 Jul;78(10):714-723. doi: 10.1002/pros.23515. Epub 2018 Mar 26.

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.

Keywords: pathology; AMP-activated protein kinase; castration-resistant prostate cancer; clinical specimens; metastasis; prostatic neoplasms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

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