Abstract

Retinoic acid (RA), is a promising therapeutic agent for the treatment of breast cancer. However, metabolic disorders and drug resistance reduce the efficacy of RA. In this study, we found that RA and ω-3 polyunsaturated fatty acids (ω-3 PUFAs) synergistically induced cell death in vitro and in vivo and autophagy activation. Moreover, RA-induced hypercholesterolemia was completely corrected by ω-3 PUFA supplementation. In addition, we demonstrated that the effects of this combination on the autophagic flux were independent of the two major canonic regulatory complexes controlling autophagic vesicle formation. The treatment activated Gαq-p38 MAPK signaling pathways, which resulted in autophagy of breast cancer cells. Knockdown of Gαq or P38 expression prevented RA and ω-3 PUFAs from inducing autophagy. Data indicated that Gαq-p38activation was mediated by the co-activation of GPR40 and RARα in lipid rafts, rather than by the activation of GPR120, RARβ, or RARγ. The results of this study suggest that hyperlipidemic drug side effects may be ameliorated by the administration of ω-3 PUFAs. Thus, the therapeutic indexes of the corresponding drugs may be increased.

Highlights

  • Retinoic acid (RA), the major bioactive metabolite of vitamin A, plays an important role in cell growth and differentiation [1]

  • This was attributed to these triple-negative breast cancer (TNBC) cells being more aggressive than the other cell lines and resistant to RA therapy [14]

  • These results indicate that ω-3 PUFAs potentiated RA-induced cell death and increased RA sensitivity

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Summary

Introduction

Retinoic acid (RA), the major bioactive metabolite of vitamin A, plays an important role in cell growth and differentiation [1]. Clinical trials in breast cancer patients have been disappointing; because of low efficacy, metabolic disorders, and drug resistance, especially in ER-negative breast cancer [2]. Metabolic disorders are key risk factors for breast cancer, and several clinical investigations have shown a significant association between metabolic syndrome and breast cancer in women [3, 4]. Statins and fibrates, which are most commonly used to treat metabolic dysfunction, have been shown to potentiate the anti-tumor activity of RA [5, 6]. This suggests that administering RA in combination with lipid-or cholesterol-lowering drugs may be an effective anti-tumor strategy in breast cancer treatment

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