Acyl-CoA synthetase long-chain 3-mediated fatty acid oxidation is required for TGFβ1-induced epithelial-mesenchymal transition and metastasis of colorectal carcinoma

Abstract

Cancer cells frequently undergo metabolic reprogramming to support tumorigenicity and malignancy, which is recognized as a hallmark of cancer. In addition to glycolysis and glutaminolysis, alterations in fatty acid (FA) metabolism have received increasing concerns in the past few years. Recently, accumulating evidence has shown that fatty acid β-oxidation (FAO) is abnormally activated in various tumors, which is associated with the machinery of proliferation, stemness, metastasis, and radiochemotherapeutic resistance of cancer cells. Acyl-CoA synthetases 3 (ACSL3) belongs to a family of enzymes responsible for converting free long-chain FAs into fatty acyl-CoA esters, which act as substrates both for lipid synthesis and FAO. Here, we demonstrate that transforming growth factor beta 1 (TGFβ1) induces the up-regulation of ACSL3 through sterol regulatory element-binding protein 1 (SREBP1) signaling to promote energy metabolic reprogramming in colorectal carcinoma (CRC) cells. ACSL3 mediates the epithelial mesenchymal transition (EMT) and metastasis of CRC cells by activation of FAO pathway to produce ATP and reduced nicotinamide adenine dinucleotide phosphate (NADPH), which sustain redox homeostasis and fuel cancer cells for invasion and distal metastasis. Thus, targeting ACSL3 and FAO metabolic pathways might be exploited for therapeutic gain for CRC and other FAs- addicted cancers.

The miR-33a-5p/CROT axis mediates ovarian cancer cell behaviors and chemoresistance via the regulation of the TGF-β signal pathway

“…Therefore, we presumed that the miR-33a-5p/ CROT axis plays an important role in mediating OC cell behaviors. Furthermore, the positive regulation of TGF-b on fatty acid oxidation has been observed in breast and colorectal cancer cells (42,43), implying that TGF-b may also be involved in CROT-mediated OC cell behaviors. Indeed, GSEA enrichment analysis showed the negative relationship between CROT and TGF-b signaling pathway.…”

circCAPRIN1 interacts with STAT2 to promote tumor progression and lipid synthesis via upregulating ACC1 expression in colorectal cancer

“…Little is known about the regulatory role of lipogenesis genes in EMT. Transforming growth factor beta 1 (TGFβ1) has been reported to induce the up‐regulation of acyl‐CoA synthetase long‐chain 3 (ACSL3) expression promoting metabolic reprogramming in colorectal carcinoma (CRC) cells, ACSL3 also mediates EMT and metastasis of CRC cells by activating the fatty acid β‐oxidation (FAO) pathway, which stimulates ATP production and inhibits the level of nicotinamide adenine dinucleotide phosphate (NADPH) [ 69 ]. Previous study has shown that TGFβ and leptin can inhibit the activity of ACC1 through AMPK‐catalyzed phosphorylation of ACC1 at Ser79, thereby promoting EMT, ACC1 inhibition combined with concomitantly increased acetylation of SMAD2, which is triggered by accumulated acetyl‐CoA, mediates TGFβ‐induced EMT [ 70 ].…”

DHRS2 inhibits cell growth and metastasis in ovarian cancer by downregulation of CHKα to disrupt choline metabolism

“…The deregulation of choline metabolism is intensively involved in the pathogenesis and development of cancers, and thus is considered to be one of the metabolic hallmarks of cancer [ 31 – 34 ]. Deregulation of choline metabolism contributes to tumorigenesis, progression, invasiveness, and therapeutic resistance [ 35 , 36 ].…”