Abstract 4963: A distinct AMP-activated protein kinase phosphorylation site is associated with metastasis and castration-resistance in prostate cancer

Abstract

Abstract AMP-activated protein kinase (AMPK) is a critical regulator of cellular metabolism and plays important role in the development and progression of several human diseases including cancer. We have previously shown that AMPKα activity is significantly inhibited by Ser-485/491 phosphorylation in cell culture and in vivo models of metastatic and castration-resistant prostate cancer. To determine potential translatability, we investigated AMPKα-Ser-485/491 phosphorylation status in clinical prostate cancer specimens and its correlation with metastasis and progression to castration-resistance. Metastasis and matched primary tumor specimens from 45 metastatic prostate cancer patients, 31.1% of which were post-androgen deprivation therapy failure (castration-resistant prostate cancer), and primary tumor specimens from 30 non-metastatic, hormone-dependent prostate cancer patients with undetectable PSA for a mean of 97.1 ± 17.5 months were obtained from the University Hospitals Case Medical Center Pathology Archive. Slides were cut from paraffin blocks, immunostained for p-Ser-485/491 AMPKα and total AMPKα, analyzed by a pathologist, and statistical significance determined by T-test, Kruskal-Wallis test, Fisher's exact test, or Chi-Square test. Mean pre-diagnostic biopsy PSA was 6.5 ng/mL (range 1.20-25.3 ng/mL) in non-metastatic patients and 501.9 ng/mL (range 1.82-3200 ng/mL) in metastatic patients (p < 0.0001). Mean total Gleason score of primary tumors was 6.5 in the non-metastatic group and 8.2 in the metastatic group (p < 0.0001); primary prostate tumor volume (mean ± S.D.) was 22.1 ± 19.5% in the non-metastatic group and 68.1 ± 28.7% in the metastatic group (p < 0.0001). The intensity of overall p-Ser-485/491 AMPKα staining and the number of p-Ser-485/491 AMPKα positively-stained cells was significantly increased in primary prostate tumors (p = 0.0003 and p = 0.0008, respectively) and metastases (p = 0.0011 and p = 0.0062, respectively) of metastatic prostate cancer patients when compared to staining of primary tumor specimens from non-metastatic prostate cancer patients. Further, the intensity of overall p-Ser-485/491 AMPKα staining increased 2.21-fold (p = 0.0050) and the number of p-Ser-485/491 AMPKα positively-stained cells increased 1.77-fold (p = 0.0041) in castration-resistant metastatic prostate cancer specimens compared to androgen-dependent prostate cancer specimens. Therefore, AMPKα Ser-485/491 phosphorylation is associated with metastasis and castration-resistance in clinical prostate cancer and may be a novel target for treatment. Citation Format: Melissa A. Babcook, Mahmut Akgul, Seunghee Margevicius, Gregory T. MacLennan, Pingfu Fu, Robert Abouassaly, Sanjay Gupta. A distinct AMP-activated protein kinase phosphorylation site is associated with metastasis and castration-resistance in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4963.