Research: GELSOMINO and COLLEAGUES,

Listed in Issue 237

Abstract

GELSOMINO and COLLEAGUES,  (1)Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy. dario.ghigo@unito.it investigated whether omega-3 polyunsaturated  fatty acids (PUFAs) affected the response to chemotherapy in multidrug resistant (MDR) tumours.

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 polyunsaturated fatty acids (PUFAs), which modulate cholesterol homeostasis in dyslipidaemia syndromes and have chemopreventive effects in colon cancer, may affect the response to chemotherapy in multidrug resistant (MDR) tumours.

Methodology

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.

Conclusion

Our work describes a new biochemical effect of omega 3 PUFAs, which can be useful to overcome chemo-resistance in MDR colon cancer cells.

References

Gelsomino G(1), Corsetto PA, Campia I, Montorfano G, Kopecka J, Castella B, Gazzano E, Ghigo D, Rizzo AM, Riganti C. Omega 3 fatty acids chemosensitize multidrug resistant colon cancer cells by down-regulating cholesterol synthesis and altering detergent resistant membranes  composition. Mol Cancer. 12:137. doi: 10.1186/1476-4598-12-137.  Nov 13 2013.

Comment

These results demonstrate that Omega 3 PUFAs were able to restore the antitumor effects of different chemotherapeutic drugs and restored a proper tumor-immune system recognition in response to chemotherapy in multidrug resistant (MDR) colon cancer tumours.

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