Zhu Shenglong, Lin Guangxiao, Song Ci, Wu Yikuan, Feng Ninghan, Chen Wei, He Zhao, Chen Yong Q
State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China.
School of Food Science and Technology, Jiangnan University, Wuxi, China.
Oncotarget. 2017 Nov 22;8(65):109135-109150. doi: 10.18632/oncotarget.22629. eCollection 2017 Dec 12.
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 and 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.
视黄酸（RA）是一种很有前景的治疗乳腺癌的药物。然而，代谢紊乱和耐药性会降低RA的疗效。在本研究中，我们发现RA与ω-3多不饱和脂肪酸（ω-3 PUFAs）协同诱导细胞死亡并激活自噬。此外，补充ω-3 PUFA可完全纠正RA诱导的高胆固醇血症。此外，我们证明了这种组合对自噬通量的影响独立于控制自噬囊泡形成的两个主要经典调节复合物。该治疗激活了Gαq-p38 MAPK信号通路，导致乳腺癌细胞自噬。敲低Gαq或P38表达可阻止RA和ω-3 PUFAs诱导自噬。数据表明，Gαq-p38激活是由脂质筏中GPR40和RARα的共同激活介导的，而不是由GPR120、RARβ或RARγ的激活介导的。本研究结果表明，服用ω-3 PUFAs可能会改善高脂血症药物的副作用。因此，相应药物的治疗指数可能会提高。
