MACC1 decreases the chemosensitivity of gastric cancer cells to oxaliplatin by regulating FASN expression

Abstract

The effect of chemotherapeutic agents is limited as a result of drug resistance, which demands prompt solutions provided by clinical studies. To date, the underlying mechanisms of chemotherapy resistance are relatively unknown. Metastasis-associated in colon cancer 1 (MACC1) is an oncogene associated with the progression and prognosis of gastric cancer (GC). Bioinformatic analysis revealed that MACC1 is positively associated with fatty acid synthase (FASN), a major enzyme of lipogenesis, and drives chemoresistance to oxaliplatin in GC. Similar findings were demonstrated in two GC cell lines (BGC-823 and MKN-28) with MACC1 ectopic expression. We next employed FASN inhibitor C75 or siFASN (small interfering RNA targeted to FASN) to block endogenous fatty acid metabolism and it was revealed that cell proliferation and chemoresistance to oxaliplatin induced by MACC1 upregulation were attenuated by FASN blockade to various extents. Conclusively, these outcomes highlight a novel role of MACC1 in GC cell lipogenesis, and suggest that MACC1 may be an attractive target to decrease oxaliplatin resistance in GC.

Comprehensive Multi-Omics Analysis Reveals Aberrant Metabolism of Epstein–Barr-Virus-Associated Gastric Carcinoma

“…We speculate that alteration of unsaturated fatty acid composition and fatty acid elongation affects the physical and chemical properties of lipids. Previous studies reported the overexpression of fatty acid synthase (FASN) in cancer [54,55]. In addition to the length of the fatty acid, the degree of unsaturation of fatty acid was also considered to affect the growth of tumor cells [56].…”

Gastric cancer cells escape metabolic stress via the DLC3/MACC1 axis

“…MACC1, as the name implies, was first identified as a pro-metastatic transcriptional factor 33. Whereafter, more malignant functions of MACC1 have been discovered, including proliferation 34, angiogenesis 30, chemoresistance 35, and metabolic remodeling 2, suggesting its potential as a therapeutic target. Previously, we discovered that MACC1 mRNA was stabilized by its associated lncRNA MACC1-AS1 via AMPK/Lin28 under metabolic stress 17.…”

Restoring Treatment Response in Colorectal Cancer Cells by Targeting MACC1-Dependent ABCB1 Expression in Combination Therapy

“…Its expression in the primary tumors drives metastasis formation, allowing the stratification of high-risk patients even at early stages (10). Moreover, besides inducing metastasis formation, MACC1 expression is also associated with increased resistance to standard and targeted therapeutics in several cancer types, including CRC (12)(13)(14)(15). After first describing the promoter region and expression regulation of MACC1 in CRC (16) we identified mevastatin as transcriptional inhibitor of MACC1 expression in a high-throughput drug screening, and confirmed the same effect for the FDA-approved lovastatin in vitro, as well as in xenograft mouse models for metastasis formation (17).…”