Lipid pathway deregulation in advanced prostate cancer

Abstract

The link between prostate cancer (PC) development and lipid metabolism is well established, with AR intimately involved in a number of lipogenic processes involving SREBP1, PPARG, FASN, ACC, ACLY and SCD1. Recently, there is growing evidence implicating the role of obesity and peri-prostatic adipose tissue (PPAT) in PC aggressiveness and related mortality, suggesting the importance of lipid pathways in both localised and disseminated disease. A number of promising agents are in development to target the lipogenic axis in PC, and the likelihood is that these agents will form part of combination drug strategies, with targeting of multiple metabolic pathways (e.g. FASN and CPT1), or in combination with AR pathway inhibitors (SCD1 and AR).

Sterculic Acid: The Mechanisms of Action beyond Stearoyl-CoA Desaturase Inhibition and Therapeutic Opportunities in Human Diseases

“…MUFAs are the main contributor to total membrane phospholipids and cholesterol esters. Pharmacological inhibition of SCD1 reduces lipid and MUFAs synthesis, suggesting that SCD1 is a master regulator of membrane composition [21]. This fact points out that SCD1 is a central element of lipid metabolism and body weight control [14].…”

“…SREBP1 is the master regulator in fatty acid metabolism, and its activation has been linked to obesity, fatty liver disease, insulin resistance, autoimmune diseases, as well as cancer development. SREBP1 controls SCD1 expression [21,26], and therefore factors activating SREBP1 signaling, such as Inflammatory pathway is shown in green. SCD1 inhibition reduces the pro-inflammatory environment and nuclear factor kappa-B (NFκB) signaling to reduce cell proliferation, while NFκB signaling activation promotes transcription factors binding to SCD1 promotor and gene expression.…”

“…SREBP1 is the master regulator in fatty acid metabolism, and its activation has been linked to obesity, fatty liver disease, insulin resistance, autoimmune diseases, as well as cancer development. SREBP1 controls SCD1 expression [21,26], and therefore factors activating SREBP1 signaling, such as carbohydrate intake, activate SCD1 as expected [27]. LXRs are other factors that control SCD1 expression.…”

“…SCDs are overexpressed in many cancer types [14,59,60] and SCD1 expression is associated with the reduction of relapse-free survival of patients of breast cancer [61]. SCD1 activity increases MUFAs levels in cell membrane to promote cell viability [21]. For example, SCD1 is overexpressed in samples of patients with anaplastic thyroid carcinoma (ATC) and well-differentiated thyroid carcinomas, and its expression correlates with tumor aggressiveness and poor prognosis in human hepatocellular carcinoma (HCC) patients [14,40,62].…”

Speckle‐type POZ protein suppresses lipid accumulation and prostate cancer growth by stabilizing fatty acid synthase

“…As such, cellular metabolic disorders are a hallmark of cancer . FASN is critical for maintaining lipid homeostasis in PCa . Recent systematic sequencing studies revealed that recurrent somatic mutations are key features of PCa, and SPOP was the most commonly mutated gene .…”