Omega 3 fatty acids chemosensitize multidrug resistant colon cancer cells by down-regulating cholesterol synthesis and altering detergent resistant membranes composition.
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.
Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy. dario.ghigo@unito.it.
Giada
G
Gelsomino
Paola A
PA
Corsetto
Ivana
I
Campia
Gigliola
G
Montorfano
Joanna
J
Kopecka
Barbara
B
Castella
Elena
E
Gazzano
Dario
D
Ghigo
Angela M
AM
Rizzo
Chiara
C
Riganti
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000378:metabolism / Q000494:pharmacology*; D015536:Down-Regulation; D004317:Doxorubicin / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D015118:Eicosapentaenoic Acid / Q000378:metabolism / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D010766:Phosphorylation; D054875:Ubiquitination
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004281:Docosahexaenoic Acids; D004317:Doxorubicin; D002784:Cholesterol; D015118:Eicosapentaenoic Acid; D006903:Hydroxymethylglutaryl CoA Reductases