Complementary ACSL isoforms contribute to a non-Warburg advantageous energetic status characterizing invasive colon cancer cells

Abstract

Metabolic reprogramming is one of cancer hallmarks. Here, we focus on functional differences and individual contribution of acyl coA synthetases (ACSL) isoforms to the previously described ACSL/stearoyl-CoA desaturase (ACSL1/ACSL4/SCD) metabolic network causing invasion and poor prognosis in colorectal cancer (CRC). ACSL4 fuels proliferation and migration accompanied by a more glycolytic phenotype. Conversely, ACSL1 stimulates invasion displaying a lower basal respiratory rate. Acylcarnitines elevation, polyunsaturated fatty acids (PUFA) lower levels, and monounsaturated fatty acids (MUFA) upregulation characterize the individual overexpression of ACSL1, ACSL4 and SCD, respectively. However, the three enzymes simultaneous overexpression results in upregulated phospholipids and urea cycle derived metabolites. Thus, the metabolic effects caused by the network are far from being caused by the individual contributions of each enzyme. Furthermore, ACSL/SCD network produces more energetically efficient cells with lower basal respiration levels and upregulated creatine pathway. These features characterize other invasive CRC cells, thus, ACSL/SCD network exemplifies specific metabolic adaptations for invasive cancer cells.

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

“…3, with the asterisk marks indicating statistically significant associations with patient prognosis. Upregulation of ACSL1 was found in multiple types of cancer, including colon (11,12), breast (13) and liver (14,15) cancer, and myeloma (16), while downregulation was found in lung squamous cell carcinoma (17). More importantly, ACSL1 overexpression was associated with a poor clinical outcome in colon cancer patients (18).…”

“…Like those of ACSL1, the majority of studies of ACLS4 favor an oncogenic role. ACSL4 has been shown to be overexpressed in multiple cancer types, including colon (11,19), breast (20), liver (21-23) and prostate (24) cancer, while another study has shown its downregulation in gastric cancer (25). In terms of patient survival outcome, ACSL4 overexpression predicted poorer patient survival in stage II colon cancer [together with upregulated stearoyl-CoA desaturase (SCD)] (12) and in liver cancer (together with downregulated growth arrest and DNA damage inducible β) (21).…”

“…Several studies highlighted that ACSLs stimulated proliferation in cancer cells. 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).…”

“…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.…”

Targeting the lipid metabolic axis ACSL/SCD in colorectal cancer progression by therapeutic miRNAs: miR-19b-1 role

“…The oxygen consumption rate (OCR) was monitored as an indicator of mitochondrial respiration with an XF96 extracellular flux analyzer using the XF Cell Mito stress test kit according to the manufacturer's instructions (Seahorse Biosciences, North Billerica, MA). Cells were seeded into XF96 plates with DMEM 10% FBS at a density of 90,000 cells per well for SW620 cells, as described in (24), and transfected the following day with mimic miRNAs (30 nM) using Lipofectamine 2000. Upon several washes, medium was replaced for 1 h prior to assay with Krebs-Henseleit buffer (111 mM NaCl, 4.7 mM KCl, 1.25 mM CaCl 2 , 2 mM MgSO 4 , and 1.2 mM NaH 2 PO 4 ) supplemented with 2.5 mM glucose, 0.5 mM carnitine, and 5 mM HEPES, as FA oxidation (FAO) medium.…”