Omega 3 fatty acids chemosensitize multidrug resistant colon cancer cells by down-regulating cholesterol synthesis and altering detergent resistant membranes composition.
Omega 3 fatty acids chemosensitize multidrug resistant colon cancer cells by down-regulating cholesterol synthesis and altering detergent resistant membranes composition.
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DOI：
10.1186/1476-4598-12-137
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发表时间：
2013-11-13
期刊：
影响因子：
37.3
通讯作者：
Riganti C
中科院分区：
文献类型：
--
作者：
Gelsomino G;Corsetto PA;Campia I;Montorfano G;Kopecka J;Castella B;Gazzano E;Ghigo D;Rizzo AM;Riganti C
p -糖蛋白（Pgp）和多药耐药相关蛋白1 （MRP1）是两种参与结肠癌多药耐药的膜转运蛋白，其活性随着质膜和洗涤剂耐药膜（DRMs）中胆固醇含量的增加而增加。omega - 3多不饱和脂肪酸（PUFAs）在血脂异常综合征中调节胆固醇稳态并在结肠癌中具有化学预防作用，但它是否会影响多药耐药（MDR）肿瘤对化疗的反应，尚无研究。我们研究了omega - 3 PUFAs二十二碳六烯酸（DHA）和二十碳五烯酸（EPA）对人化疗敏感结肠癌HT29细胞及其耐多药对抗性HT29-dx细胞的影响。过表达Pgp和MRP1的MDR细胞，由于泛素E3连接酶Trc8的表达较低，导致MDR细胞胆固醇代谢失调，3-羟基-3-甲基戊二酰辅酶a还原酶（HMGCoAR）泛素化率较低，胆固醇合成较高，胆固醇含量较高。我们发现DHA和EPA重新激活了MDR细胞中的Trc8 E3连接酶，使HMGCoAR的泛素化率恢复到与化学敏感细胞相当的水平，减少了DRMs中胆固醇的合成和掺入。Omega - 3 PUFAs被纳入MDR细胞的全脂质和DRMs中，并改变了这些隔室的脂质组成。他们减少了DRMs中含有的Pgp和MRP1的数量，降低了转运蛋白的活性，恢复了不同化疗药物的抗肿瘤作用，恢复了MDR细胞对化疗的适当肿瘤免疫系统识别。我们的工作描述了omega - 3 PUFAs的一种新的生化作用，它可以用于克服耐多药结肠癌细胞的化学耐药。
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. 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. 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. Our work describes a new biochemical effect of omega 3 PUFAs, which can be useful to overcome chemoresistance in MDR colon cancer cells.
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影响因子：
4.4
作者：
Chang CL;Deckelbaum RJ
通讯作者：
Deckelbaum RJ
影响因子：
4.5
作者：
Corsetto PA;Montorfano G;Zava S;Jovenitti IE;Cremona A;Berra B;Rizzo AM
通讯作者：
Rizzo AM
影响因子：
8
作者：
Campia, I.;Gazzano, E.;Riganti, C.
通讯作者：
Riganti, C.
影响因子：
3.7
作者：
Bacso, Z;Nagy, H;Szabó, G
通讯作者：
Szabó, G
影响因子：
3.6
作者：
Granci, Virginie;Cai, Fang;Pichard, Claude
通讯作者：
Pichard, Claude