Journal Article

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

Kopecka, Joanna, Campia, Ivana, Ghigo, Dario, Rizzo, Angela M, Gelsomino, Giada, Castella, Barbara, Corsetto, Paola A, Gazzano, Elena, Riganti, Chiara, Montorfano, Gigliola

2013

Overview

Background The 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. Methods We 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. Results MDR 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. Conclusions Our work describes a new biochemical effect of omega 3 PUFAs, which can be useful to overcome chemoresistance in MDR colon cancer cells.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: Analysis / Antibiotics, Antineoplastic - therapeutic use / ATP-Binding Cassette, Sub-Family B, Member 1 - genetics / ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism / Biological products industry / Biomedical and Life Sciences / Biomedicine / Breast cancer / Cancer / Cancer cells / Cancer Research / Cell Line, Tumor / Cell Membrane - metabolism / Cholesterol / Cholesterol - biosynthesis / Colon cancer / Colonic Neoplasms - drug therapy / Colonic Neoplasms - genetics / Colonic Neoplasms - immunology / Colonic Neoplasms - metabolism / Colorectal cancer / Diet therapy / Docosahexaenoic Acids - metabolism / Docosahexaenoic Acids - pharmacology / Down-Regulation / Doxorubicin - therapeutic use / Drug resistance / Drug resistance in microorganisms / Drug Resistance, Multiple / Drug Resistance, Neoplasm / Eicosapentaenoic Acid - metabolism / Eicosapentaenoic Acid - pharmacology / Fatty acids / Gene Expression Regulation, Neoplastic / Health aspects / HT29 Cells / Humans / Hydroxymethylglutaryl CoA Reductases - metabolism / Ligases / Medical research / Membranes / Omega-3 fatty acids / Oncology / Phosphorylation / Physiological aspects / Prevention / Ubiquitin / Ubiquitination / Unsaturated fatty acids