Tumor-suppressive functions of long-chain acyl-CoA synthetase 4 in gastric cancer

Abstract

Long chain acyl CoA synthetase 4 (ACSL4) is a key enzyme in fatty acid metabolism with marked preference for arachidonic acid (AA). Recent reports have implicated its crucial roles in tumorigenesis. However in gastric cancer (GC), the expression and function of ACSL4 remain unclear. In the present study, we identified ACSL4 as a potential tumor suppressor in GC. The ACSL4 expression in GC samples was evaluated by realtime PCR and immunohistochemistry. The results indicated that the mRNA and protein levels of ACSL4 were frequently downregulated in cancer tissues compared with the adjacent non-cancerous mucosa control tissues. Cell-based functional assays exhibited that ectopic expression of ACSL4 inhibits cell growth, colony formation and cell migration, whereas ACSL4 knockdown enhanced these effects. In a nude mice model, ACSL4 knockdown also promoted subcutaneous xenografts' growth in vivo. Moreover, western blot analysis revealed that ACSL4 expression had a significant effect on FAK and P21 protein level. These findings suggest that ACSL4 plays a tumorsuppressive role and could be a potential therapeutic target in GC.

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

“…In general, these findings were in line with the observations that ACSLs are upregulated in cancer. However, in a few exceptions, knockdown of ACSL1 or ACSL4 with specific small interfering RNA promoted lung (37) or gastric (25) cancer cell growth, respectively, and in vivo xenograft growth of gastric tumors (25).…”

“…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).…”

Immunohistochemical staining reveals differential expression of ACSL3 and ACSL4 in hepatocellular carcinoma and hepatic gastrointestinal metastases

“…Particularly so since ACSL4 is required for ferroptosis which has a potential tumour-suppressive function. As an example, ACSL4 is significantly down-regulated in gastric cancer compared with cancer-adjacent normal gastric mucosa [36]. Moreover, transient overexpression of recombinant ACSL4 in gastric cancer cell lines significantly inhibited cell growth, proliferation and migration in vitro, whereas knockdown of ACSL4 induced reciprocal effects [36].…”

“…Anti-ACSL3 rabbit polyclonal IgG antiserum (catalogue# PA5-42883) was purchased from Thermo Fisher Scientific, U.K.; its specificity has been validated in short hairpin RNAi knockdown experiments [37]. Anti-ACSL4 rabbit polyclonal IgG antiserum (catalogue# 22401-1-AP) was obtained from Proteintech Europe (Manchester, U.K.), its antigen specificity has been validated by both recombinant overexpression and siRNAi studies [36], and it has been used previously for detecting ACSL4 overexpression in HCC [57]. Liver tissue microarrays (#LV2091) were purchased from US Biomax (Rockville, U.S.A.).…”

“…ACSL4 is also associated with the ER and lipid droplets [30,31] but endosomal [32], plasma membrane [30], peroxisomal [33] and secretory vesicle [29] localisations have also been reported. Importantly, there is emerging evidence that dysregulated expression of both ACSL3 and ACSL4 is associated with disease and especially with cancer [15,28,[34][35][36][37][38]. ACSL3 can promote cancer cell survival through amplified fatty acid β-oxidation [5,37] and increased arachidonic acid-dependent prostaglandin synthesis [39], both of which can drive tumour growth.…”