Lipid droplets induced by secreted phospholipase A2 and unsaturated fatty acids protect breast cancer cells from nutrient and lipotoxic stress
Lipid droplets induced by secreted phospholipase A2 and unsaturated fatty acids protect breast cancer cells from nutrient and lipotoxic stress
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DOI：
10.1016/j.bbalip.2017.12.006
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发表时间：
2018-03-01
影响因子：
4.8
通讯作者：
Petan, Toni
中科院分区：
文献类型：
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作者：
Jarc, Eva;Kump, Ana;Petan, Toni
由 Ras 癌基因驱动的癌细胞从环境中清除不饱和脂肪酸 (FA)，以应对营养压力。人类 X 组分泌的磷脂酶 A(2) (hGX sPLA(2)) 从膜磷脂中释放 FA，刺激 Ras 驱动的三阴性乳腺癌 (TNBC) 细胞中的脂滴 (LD) 生物发生，并使它们在饥饿期间生存。在这里，我们研究了 hGX sPLA(2) 和不饱和 FA 诱导的 LD 在保护 TNBC 细胞免受营养应激方面的作用。我们发现 hGX sPLA(2) 从 TNBC 细胞中释放出不饱和 FA 的混合物，包括 omega-3 和 omega-6 多不饱和 FA (PUFA)。低微摩尔浓度的不饱和 FA（包括 PUFA）诱导的 LD 的饥饿诱导分解与防止细胞死亡有关。有趣的是，脂肪甘油三酯脂肪酶 (ATGL) 在饥饿期间导致 LD 分解，但它并不是 hGX sPLA(2) 和不饱和 FA 的促生存作用所必需的。高微摩尔浓度的 PUFA（而非 OA）会诱导 TNBC 细胞氧化应激依赖性细胞死亡。抑制三酰甘油 (TAG) 合成可抑制 LD 生物发生并增强 PUFA 诱导的细胞损伤。相反，hGX sPLA(2) 刺激 LD 生物发生和 ATGL 消耗抑制 LD 分解可减少 PUFA 诱导的氧化应激和细胞死亡。最后，脂质组学分析表明，通过 sPLA(2) 诱导的 TAG 重塑将 PUFA 隔离在 LD 中，并通过抑制 ATGL 介导的 TAG 脂解作用将 PUFA 保留在 LD 中，从而防止 PUFA 脂毒性。因此，LD 是抗氧化剂和促生存细胞器，可保护 TNBC 细胞免受营养和脂毒性应激，并成为新型治疗干预措施的有吸引力的目标。
Cancer cells driven by the Ras oncogene scavenge unsaturated fatty acids (FAs) from their environment to counter nutrient stress. The human group X secreted phospholipase A(2) (hGX sPLA(2)) releases FAs from membrane phospholipids, stimulates lipid droplet (LD) biogenesis in Ras-driven triple-negative breast cancer (TNBC) cells and enables their survival during starvation. Here we examined the role of LDs, induced by hGX sPLA(2) and unsaturated FAs, in protection of TNBC cells against nutrient stress. We found that hGX sPLA(2) releases a mixture of unsaturated FAs, including omega-3 and omega-6 polyunsaturated FAs (PUFAs), from TNBC cells. Starvation-induced breakdown of LDs induced by low micromolar concentrations of unsaturated FAs, including PUFAs, was associated with protection from cell death. Interestingly, adipose triglyceride lipase (ATGL) contributed to LD breakdown during starvation, but it was not required for the pro-survival effects of hGX sPLA(2) and unsaturated FAs. High micromolar concentrations of PUFAs, but not OA, induced oxidative stress-dependent cell death in TNBC cells. Inhibition of triacylglycerol (TAG) synthesis suppressed LD biogenesis and potentiated PUFA-induced cell damage. On the contrary, stimulation of LD biogenesis by hGX sPLA(2) and suppression of LD breakdown by ATGL depletion reduced PUFA-induced oxidative stress and cell death. Finally, lipidomic analyses revealed that sequestration of PUFAs in LDs by sPLA(2)-induced TAG remodelling and retention of PUFAs in LDs by inhibition of ATGL-mediated TAG lipolysis protect from PUFA lipotoxicity. LDs are thus antioxidant and pro survival organelles that guard TNBC cells against nutrient and lipotoxic stress and emerge as attractive targets for novel therapeutic interventions.