RA and ω-3 PUFA co-treatment activates autophagy in cancer cells

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.

Anticancer effects of n-3 EPA and DHA and their endocannabinoid derivatives on breast cancer cell growth and invasion

“…Many studies investigating the role of cannabinoids and n-6 endocannabinoids in inhibiting cancer cell proliferation suggested involvement of the MAP kinase family of signal transducers [14,15,[33][34][35][36]]. Our findings generally demonstrated that both n-3 LCPUFA and their respective n-3 endocannabinoids can also elicit changes in MAPK signalling by decreasing expression of p38 MAPK and levels of activated (phosphorylated) p38 MAPK (pp38) in BC cells.…”

“…In the case of EPA treatment, phosphorylated (activated) pp38 was significantly reduced, even though non-phosphorylated p38 levels were increased. Activation of p38 MAPK by cannabinoids has been reported previously [16,17,[34][35][36][37] and it is usually thought this activation leads to increased apoptosis, but here we show down-regulation of both total p38 MAPK and activated pp38 by n-3 LCPUFA and to depend on the stimuli, cell type, and/or the particular enzyme isoforms present (reviewed in [38]). In the current study we did not determine the latter.…”

1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3-(2-(dimethylamino)ethyl)imidazolidin-2-one (ZX-42), a novel ALK inhibitor, induces apoptosis and protective autophagy in H2228 cells

“…CQ can inhibit the degradation of autophagosomes to inhibit the occurrence of autophagy. [22] Therefore, after adding CQ, the autophagosomes can aggregate in the cells, and the positive rate of MDC will be increased. As shown in Figure 8b, c, ZX-42 enhanced the amount of autophagosomes in a dose-dependent manner, and the autophagy inhibitor CQ increased the production of autophagosomes.…”

PA and OA Induce Abnormal Glucose Metabolism by Inhibiting KLF15 in Adipocytes

“…Moreover, PA-induced abnormal glucose metabolism through a GPR120/P-p38 MAPK/KLF15 signal pathway in 3T3-L1 adipocytes, while GPR40 had no effects on P-p38 MAPK under PA stimulation. Interestingly but inconsistently, it has been reported that Gq-p38 activation was mediated by GPR40 rather than GPR120 involving in autophagy of breast cancer cells [28] . Probably, the activation mechanism of p38 MAPK may be distinct in different cell type or pattern.…”