Metformin effects on biochemical recurrence and metabolic signaling in the prostate

Abstract

Background: Metformin has received considerable attention as a potential anti-cancer agent. Animal and in-vitro prostate cancer (PCa) models have demonstrated decreased tumor growth with metformin, however the precise mechanisms are unknown. We examine the effects of metformin on PCa biochemical recurrence (BCR) in a large clinical database followed by evaluating metabolic signaling changes in a cohort of men undergoing prostate needle biopsy (PNB).

Methods: Men treated for localized PCa were identified in a comprehensive clinical database between 2001 and 2010. Cox regression was performed to determine association with BCR relative to metformin use. We next identified a separate case-control cohort of men undergoing prostate needle biopsy (PNB) stratified by metformin use. Differences in mean IHC scores were compared with linear regression for phosphorylated IR, IGF-IR, AKT, and AMPK.

Results: One thousand seven hundred and thirty four men were evaluated for BCR with mean follow up of 41 months (range 1-121 months). "Ever" metformin use was not associated with BCR (HR 1.12, 0.77-1.65), however men reporting both pre/post-treatment metformin use had a 45% reduction in BCR (HR = 0.55 (0.31-0.96)). For the tissue-based study, 48 metformin users and 42 controls underwent PNB. Significantly greater staining in phosphorylated nuclear (p-IR, p-AKT) and cytoplasmic (p-IR, p-IGF-1R) insulin signaling proteins were seen in patients with PCa detected compared to those with negative PNB (P-values all <0.006). When stratified by metformin use, IGF-1R remained significantly elevated (P = 0.01) in men with PCa detected whereas p-AMPK (P = 0.05) was elevated only in those without PCa.

Conclusion: Metformin use is associated with reduced BCR after treatment of localized PCa when considering pre-diagnostic and cumulative dosing. In men with cancer detected on PNB, insulin signaling markers were significantly elevated compared to negative PNB patients. The finding of IGF-1R elevation in positive PNBs versus p-AMPK elevation in negative PNBs suggests altered metabolic pathway activation precipitated by metformin use.

Keywords: AMPK; insulin signaling; metformin; prostate cancer; veterans affairs.

Figure 1. Proposed model of insulin signaling relative to cellular proliferation

Simplified model of proposed effects of metformin and AMPK relative to insulin signaling and cellular proliferation are shown.(15, 16, 22, 45) AMPK: AMP activated protein kinase K; IR: insulin receptor; IGF-1: insulin-like growth factor 1; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; TSC1/2: tuberous sclerosis complex 1/2; RHEB: ras homologue enriched in brain; mTOR: mammalian target of rapamycin

Figure 2. IHC staining of prostate needle biopsy specimens

Representative IHC staining from prostate needle biopsy specimens for (A) Insulin Receptor; (B) phosphorylated Insulin Receptor; (C) IGF-1 Receptor; (D) phosphorylated IGF-1 Receptor; (E) AMPK; and (F) phosphorylated AMPK. IGF-1: insulin-like growth factor 1; AMPK: AMP activated protein kinase K.