期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
卷 1861, 期 4, 页码 380-390出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbalip.2016.01.012
关键词
n-3 LCPUFA; DHA; Docetaxel; Tumor sensitization; PKC epsilon; PKC delta; ERK; Akt; Mammary tumors
资金
- Institut National de la Sante et de la Recherche Medicale (Inserm)
- Fonds Europeens de Developpement Regional (FEDER)
- Region Centre
- Lipid project ARD Biomedicaments
- Ministere de l'Enseignement Superieur et de la Recherche
- University Hospital Bretonneau, Tours
- Ligue Nationale contre le Cancer (Comites 37) Canceropole Grand Ouest
- Ligue Nationale contre le Cancer (Comite 41) Canceropole Grand Ouest
- Ligue Nationale contre le Cancer (Comite 49) Canceropole Grand Ouest
Taxanes can induce drug resistance by increasing signaling pathways such as PI3K/Akt and ERK, which promote survival and cell growth in human cancer cells. We have previously shown that long chain n-3 polyunsaturated fatty acids, such as docosahexaenoic acid (DHA, 22:6n-3) decrease resistance of experimental mammary tumors to anticancer drugs. Our objective was to determine whether DHA could increase tumor sensitivity to docetaxel by down-regulating these survival pathways. In docetaxel-treated MDA-MB-231 cells, phosphorylated-ERK1/2 levels were increased by 60% in membrane and nuclear compartments, compared to untreated cells. Our data showed that ERK1/2 activation depended on PKC activation since: i) enzastaurin (a pan-PKC inhibitor) blocked docetaxel-induced ERK1/2 phosphorylation ii) docetaxel increased PKC activity by 30% and phosphatidic acid level by 1.6-fold iii) inhibition of PKC epsilon and PKC delta by siRNA resulted in reduced phosphorylated ERK1/2 levels. In DHA-supplemented cells, docetaxel was unable to increase PKCe and 8 levels in membrane and nuclear fractions, resulting in diminished ERK1/2 phosphorylation and increased docetaxel efficacy. Reduced membrane level of PKC epsilon and PKC delta was associated with significant incorporation of DHA in all phospholipids, including phosphatidylcholine which is a major source of phosphatidic acid. Additionally, examination of the Akt pathway showed that DHA could repress docetaxel-induced Ser473Akt phosphorylation. In rat mammary tumors, dietary DHA supplementation during docetaxel chemotherapy repressed ERK and Akt survival pathways and in turn strongly improved taxane efficacy. The P-ERK level was negatively correlated with tumor regression. These findings are of potential clinical importance in treating chemotherapy-refractory cancer. (C) 2016 Elsevier B.V. All rights reserved.
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