Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Mol Cell Endocrinol. 2012 Nov 5;363(1-2):111-21. doi: 10.1016/j.mce.2012.08.005. Epub 2012 Aug 16.
Progestins induce lipid accumulation in progesterone receptor (PR)-positive breast cancer cells. We speculated that progestin-induced alterations in lipid biology confer resistance to chemotherapy. To examine the biology of lipid loaded breast cancer cells, we used a model of progestin-induced lipid synthesis. T47D (PR-positive) and MDA-MB-231 (PR-negative) cell lines were used to study progestin response. Oil red O staining of T47D cells treated with progestin showed lipid droplet formation was PR dependent, glucose dependent and reduced sensitivity to docetaxel. This protection was not observed in PR-negative MDA-MB-231 cells. Progestin treatment induced stearoyl CoA desaturase-1 (SCD-1) enzyme expression and chemical inhibition of SCD-1 diminished lipid droplets and cell viability, suggesting the importance of lipid stores in cancer cell survival. Gas chromatography/mass spectroscopy analysis of phospholipids from progestin-treated T47D cells revealed an increase in unsaturated fatty acids, with oleic acid as most abundant. Cells surviving docetaxel treatment also contained more oleic acid in phospholipids, suggesting altered membrane fluidity as a potential mechanism of chemoresistance mediated in part by SCD-1. Lastly, intact docetaxel molecules were present within progestin induced lipid droplets, suggesting a protective quenching effect of intracellular lipid droplets. Our studies suggest the metabolic adaptations produced by progestin provide novel metabolic targets for future combinatorial therapies for progestin-responsive breast cancers.
孕激素可诱导孕激素受体（PR）阳性乳腺癌细胞内脂质堆积。我们推测孕激素诱导的脂质生物学改变可导致对化疗的耐药。为了研究负载脂质的乳腺癌细胞的生物学特性，我们建立了孕激素诱导脂质合成的模型。我们使用 T47D（PR 阳性）和 MDA-MB-231（PR 阴性）细胞系来研究孕激素的反应。用孕激素处理 T47D 细胞后用油红 O 染色，显示脂滴形成是 PR 依赖性、葡萄糖依赖性的，并降低了对多西紫杉醇的敏感性。在 PR 阴性的 MDA-MB-231 细胞中未观察到这种保护作用。孕激素处理诱导硬脂酰辅酶 A 去饱和酶-1（SCD-1）酶表达，化学抑制 SCD-1 减少了脂滴和细胞活力，表明脂质储存对癌细胞存活的重要性。用孕激素处理 T47D 细胞后的磷脂气相色谱/质谱分析显示不饱和脂肪酸增加，油酸最为丰富。在多西紫杉醇处理后存活的细胞中，磷脂中的油酸也更多，这表明细胞膜流动性的改变可能是 SCD-1 介导的部分化疗耐药的潜在机制。最后，完整的多西紫杉醇分子存在于孕激素诱导的脂滴中，这表明细胞内脂滴具有保护作用，可使多西紫杉醇失活。我们的研究表明，孕激素产生的代谢适应为孕激素反应性乳腺癌的未来联合治疗提供了新的代谢靶标。
