Diet-induced alteration of fatty acid synthase in prostate cancer progression.

M Huang,T Inoue,H Tsuruta,A Koizumi,S Satoh,H Nanjo,T Sasaki,S Narita,H Nakanishi,T Habuchi,M Saito,N Tsuchiya,K Numakura

doi:10.1038/oncsis.2015.42

Abstract

Fatty acid synthase (FASN) is a cytosolic metabolic enzyme that catalyzes de novo fatty acid synthesis. A high-fat diet (HFD) is attributed to prostate cancer (PCa) progression, but the role FASN on HFD-mediated PCa progression remains unclear. We investigated the role of FASN on PCa progression in LNCaP xenograft mice fed with HFD or low-fat diet (LFD), in PCa cells, and in clinical PCa. The HFD promoted tumour growth and FASN expression in the LNCaP xenograft mice. HFD resulted in AKT and extracellular signal-regulated kinase (ERK) activation and 5' adenosine monophosphate-activated protein kinase (AMPK) inactivation. Serum FASN levels were significantly lower in the HFD group (P=0.026) and correlated inversely with tumour volume (P=0.022). Extracellular FASN release was enhanced in the PCa cells with phosphatidylinositol 3-kinase (PI3K)/mitogen-activated protein kinase (MAPK) inhibition and AMPK signalling activation. FASN inhibition resulted in decrease of PCa cell proliferation through PI3K/MAPK downregulation and AMPK activation. Furthermore, AMPK activation was associated with FASN downregulation and PI3K/MAPK inactivation. Clinically, high FASN expression was significantly associated with high Gleason scores and advanced pathological T stage. Moreover, FASN expression was markedly decreased in the PCa response to androgen deprivation therapy and chemotherapy. HFD modulates FASN expression, which may be an important mechanism in HFD-associated PCa progression. Furthermore, a critical stimulatory loop exists between FASN and the PI3K/MAPK system, whereas AMPK signalling was associated with suppression. These may offer appropriate targets for chemoprevention and cancer therapy in HFD-induced PCa.

Highlights

Prostate cancer (PCa) is the most commonly diagnosed cancer and the second most common cause of cancer-related death in the United States.[1]
Amino-4-imidazole carboxamide riboside (AICAR) treatment resulted in expression consumption in the two diet groups, the caloric consumption was of intracellular Fatty acid synthase (FASN) (270 kDa intact form) and downregulation of significantly higher in the high-fat diet (HFD) group than the low-fat diet (LFD) group the precursor (125 kDa) and mature (68 kDa) forms of sterol regulatory element-binding proteins (SREBPs)-1
The expression of FASN and SREBP-1 mRNAs was significantly lower in the LNCaP and C4-2 cells treated with LY294002 or U0126 compared with the parental cells (P o0.01; Figures 2b and c). 5-Amino-4-imidazole carboxamide riboside (AICAR), which is a pharmacological activator of AMPK, stimulated extracellular FASN release in breast cancer cells;[26] we investigated the role of AMPK signalling in FASN and SREBP-1 expression in PCa cells treated with AICAR

Summary

Introduction

Prostate cancer (PCa) is the most commonly diagnosed cancer and the second most common cause of cancer-related death in the United States.[1]. Several studies have indicated that HFD intake may affect gene expression, cellular activity and the circulating levels of biological factors through the hyperactivation of the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signalling pathways known to be involved in prostate carcinogenesis.[5,6,7,8]. Fatty acid synthase (FASN) is a metabolic enzyme that catalyzes the de novo synthesis of fatty acids; it is regulated by sterol regulatory element-binding proteins (SREBPs).[9,10,11] In addition, FASN has been shown to be upregulated by androgens and to promote LNCaP cell proliferation,[12,13] and FASN expression known to be regulated by PI3K and MAPK signalling pathways.[14,15]

Methods

Results

Conclusion