Omega 3 fatty acids chemosensitize multidrug resistant colon cancer cells by down-regulating cholesterol synthesis and altering detergent resistant membranes composition

Abstract

BackgroundThe activity of P-glycoprotein (Pgp) and multidrug resistance related protein 1 (MRP1), two membrane transporters involved in multidrug resistance of colon cancer, is increased by high amounts of cholesterol in plasma membrane and detergent resistant membranes (DRMs). It has never been investigated whether omega 3 polyunsatured fatty acids (PUFAs), which modulate cholesterol homeostasis in dyslipidemic syndromes and have chemopreventive effects in colon cancer, may affect the response to chemotherapy in multidrug resistant (MDR) tumors.MethodsWe studied the effect of omega 3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in human chemosensitive colon cancer HT29 cells and in their MDR counterpart, HT29-dx cells.ResultsMDR cells, which overexpressed Pgp and MRP1, had a dysregulated cholesterol metabolism, due to the lower expression of ubiquitin E3 ligase Trc8: this produced lower ubiquitination rate of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCoAR), higher cholesterol synthesis, higher cholesterol content in MDR cells. We found that DHA and EPA re-activated Trc8 E3 ligase in MDR cells, restored the ubiquitination rate of HMGCoAR to levels comparable with chemosensitive cells, reduced the cholesterol synthesis and incorporation in DRMs. Omega 3 PUFAs were incorporated in whole lipids as well as in DRMs of MDR cells, and altered the lipid composition of these compartments. They reduced the amount of Pgp and MRP1 contained in DRMs, decreased the transporters activity, restored the antitumor effects of different chemotherapeutic drugs, restored a proper tumor-immune system recognition in response to chemotherapy in MDR cells.ConclusionsOur work describes a new biochemical effect of omega 3 PUFAs, which can be useful to overcome chemoresistance in MDR colon cancer cells.

Natural Product Modulators to Overcome Multidrug Resistance In Cancer

“…In a recent study, 2 v-3PUFAs; docosahexaenoic acid and eicosapentaenoic acid overcame drug resistance in MDR cells toward the Pgp and MRP1 substrates, decreasing the transporters activity in response to chemotherapy (62).…”

Mechanisms by Which Pleiotropic Amphiphilic n−3 PUFA Reduce Colon Cancer Risk

“…For example, DHA and EPA reduce cholesterol synthesis in HT29 colon cancer cells [27•]. Fish oil (FO)-fed mice exhibited a ~46 % reduced cholesterol content in colonic caveolae, specialized rafts enriched in the structure protein caveolin-1, which regulate the clustering of signaling proteins such as Ras and eNOS [28].…”

658 Marine Omega-3 Polyunsaturated Fatty Acid Intake and Survival After Colorectal Cancer Diagnosis

“…[5] Supplementation of ω-3 PUFAs has been reported to enhance antitumor effects of chemotherapeutic agents in CRC. [6,7] Substantial, albeit inconsistent, evidence also suggests that ω-3 PUFAs can inhibit cancer-related cachexia by improving food intake, delaying the onset of anorexia, and preventing body weight loss. [8,9] Therefore, it is plausible that intake of marine ω-3 PUFAs could provide an opportunity to improve survival among CRC patients.…”