*4.2. Lipid Accumulation*

The changes in endogenously synthesized/exogenous lipid profiles and related enzymes have been linked to prostate cancer development and progression. Accordingly, Freedland et al. showed that mice with LAPC-4 xenografts receiving a NCKD diet had low hepatic fatty infiltration, which resulted in reduced tumor growth and longer survival [20]. Genome-wide gene expression analysis showed that the lipogenic gene ELOVL7, which possibly codes a long-chain fatty acid elongase, was overexpressed in clinical prostate cancer and regulated by SREBP1. Moreover, a HFD had been found to promote the growth of in vivo tumors of ELOLV7-expresssed prostate cancer [22]. In the aggressive and metastatic tumor progression observed in TRAMP mice receiving a Western-style diet, Llaveries et al. showed that the Western-style diet increased both the expression of the high density lipoprotein receptor SR-BI and angiogenesis [25]. Fatty acid synthase (FASN) is a cytosolic metabolic enzyme that catalyzes de novo fatty acid synthesis. Our previous study found that serum FASN levels were significantly lower and were inversely correlated with tumor volume in LNCaP xenograft mice receiving HFD [46].

A recent study has suggested that a Western-style HFD promotes metastatic prostate cancer through a prometastatic lipogenic program alteration [56]. In this study, the conditional inactivation of Pml (a suppressor of pp1 α-dependent activation of MAPK signaling) in mouse prostates changed indolent PTEN-null prostate tumors into lethal metastatic tumors with MAPK reactivation, subsequent hyperactivation of an aberrant SREBP, and a lipidomic profile alteration. Pten-/-, Pml-/- mice receiving a chow diet displayed limited lymph node metastasis. However, most mice receiving a HFD developed lymph node metastasis, while half of them had lung metastasis. Moreover, Oil Red O staining showed that the tumors in mice receiving a HFD had higher lipid accumulation compared to those in mice receiving a chow diet. Sterol responsive element binding proteins (SREBPs) have been found to be a key regulator of lipogenic genes [56]. Studies have shown that HFD feeding stimulates SREBP expression, subsequent expression of genes encoding lipogenic enzymes, and lipid accumulation in nonadipose tissues [56,84]. Therefore, Pml and SREBP-dependent lipogenic alterations may be associated with HFD-enhanced prostate cancer progression.

Although de novo lipogenesis has emerged as an important player in prostate cancer, the impact of exogenous dietary fat on intraprostatic lipid profiles and activity of lipogenic enzymes remains largely unknown. Future studies are required to elucidate the mechanisms for endogenous lipid alterations and exogenous fat accumulation on dietary fat-induced prostate cancer development and progression.
