ACSL4 promotes prostate cancer growth, invasion and hormonal resistance

Abstract

Increases in fatty acid metabolism have been demonstrated to promote the growth and survival of a variety of cancers, including prostate cancer (PCa). Here, we examine the expression and function of the fatty acid activating enzyme, long-chain fatty acyl-CoA synthetase 4 (ACSL4), in PCa. Ectopic expression of ACSL4 in ACSL4-negative PCa cells increases proliferation, migration and invasion, while ablation of ACSL4 in PCa cells expressing endogenous ACSL4 reduces cell proliferation, migration and invasion. The cell proliferative effects were observed both in vitro, as well as in vivo. Immunohistochemical analysis of human PCa tissue samples indicated ACSL4 expression is increased in malignant cells compared with adjacent benign epithelial cells, and particularly increased in castration-resistant PCa (CRPC) when compared with hormone naive PCa. In cell lines co-expressing both ACSL4 and AR, proliferation was independent of exogenous androgens, suggesting that ACSL4 expression may lead to CRPC. In support for this hypothesis, ectopic ACSL4 expression induced resistance to treatment with Casodex, via decrease in apoptosis. Our studies further indicate that ACSL4 upregulates distinct pathway proteins including p-AKT, LSD1 and β-catenin. These results suggest ACSL4 could serve as a biomarker and potential therapeutic target for CRPC.

Integrated regulatory-metabolic network model reveals critical mechanism and potential targets for Hepatocellular Carcinoma

“…There are three reactions having non-zero flux in Class 2 but zero flux in Class 1/3 (type 4), involving fatty acid activation responsible for providing adequate ATP and CoA for tumor cell growth; glycine, serine, threonine metabolism helping reduce ROS pressure through SGOC metabolic network during tumor metastasis (51), and arginine/proline metabolism, which can regulate response to nutrient and oxygen deprivation in oncogenesis thus avoiding cell apoptosis (52). Furthermore, the exploration of enzymes revealed that ACADSB (which is also indicated by previous analyses), ACSL3 and ACSL4 regulate distinct proteins like p-AKT, LSD1 and β-catenin to stimulate tumor cell proliferation (53).…”

Elevated expression of FABP3 and FABP4 cooperatively correlates with poor prognosis in non-small cell lung cancer (NSCLC)

“…Earlier studies have focused on glucose and glutamine metabolism pathways during tumor development. Latest research has suggested that fatty acid metabolism also plays an important role in various aspects of tumor cell proliferation, transformation and migration [45]. Mechanistically, the high proliferation rate of tumor cells requires a large amount of fatty acids [46], not only as energy source, but also as building blocks for large biomolecules [47, 48]; many lipid molecules can act as signaling molecules that induce carcinogenesis [49].…”

Fatty acid activation in carcinogenesis and cancer development: Essential roles of long‑chain acyl‑CoA synthetases (Review)

“…Knockdown of ACSL1, ACSL3 or ACSL4 independently decreased cell proliferation and anchorage-independent growth in multiple cancer cells and xenograft tumor growth in nude mice (11,21,31,43). By contrast, forced overexpression of these ACSLs increased cell proliferation and tumor growth (15,20,24,46,47). Furthermore, treatment with a PUFA analogue triacsin C (a potent inhibitor of ACSL1, ACSL3 and ACSL4, but not ACSL5) or other inhibitors repressed cancer cell growth in vitro and in vivo (48).…”

“…Particularly in those cancer types that originate from tissues with a higher basal level of lipid metabolism and deposition (e.g. liver, colon, breast and prostate cancer), ACSL1 (11)(12)(13)(14)(15) and ACSL4 (19)(20)(21)(22)(23)(24) were generally upregulated. These two enzymes participate in lipid anabolism and catabolism.…”