Insensitivity to atorvastatin is associated with increased accumulation of intracellular lipid droplets and fatty acid metabolism in breast cancer cells.
Insensitivity to atorvastatin is associated with increased accumulation of intracellular lipid droplets and fatty acid metabolism in breast cancer cells.
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DOI：
10.1038/s41598-018-23726-3
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发表时间：
2018-04-03
影响因子：
4.6
通讯作者：
Borgquist S
中科院分区：
文献类型：
--
作者：
Lettiero B;Inasu M;Kimbung S;Borgquist S
除了相关的降脂作用外，他汀类药物在防止乳腺癌(BC)进展方面显示出显著的抗肿瘤活性，尽管不同。为了确定不同治疗反应背后的关键途径，我们研究了他汀对阿托伐他汀表现出不同敏感性的BC细胞中脂代谢调节和中性含脂细胞质脂滴(LDS)丰度的变化。阿托伐他汀治疗后，在对阿托伐他汀不敏感的BC细胞中，累积的LD水平以剂量和时间依赖的方式反向反映边缘抗增殖效应。转录图谱排除了脂类摄取和外流的失调，这是与阿托伐他汀不同的LD蓄积和抗增殖作用相关的特定机制。值得注意的是，参与不饱和脂肪酸代谢[硬脂酰辅酶A脱饱和酶(SCD)]和胆固醇生物合成[3-羟基-3-甲基戊二酰辅酶A还原酶(HMGCR)]的基因显著上调与阿托伐他汀不敏感有关。综上所述，阿托伐他汀治疗后LDS储存中性脂质的能力增强，可能为BC细胞提供了增殖优势，并可能成为BC中他汀类药物耐药的潜在生物标志物。为了更好地理解他汀类药物抑制BC进展的分子机制，应深入探讨胆固醇生物合成和不饱和脂肪酸代谢在LD形成中的作用。
Apart from the relevant lipid-lowering effects, statins have demonstrated significant, although heterogeneous, anti-tumor activities in preventing breast cancer (BC) progression. To characterize the critical pathways behind the diverse responses to therapy, we investigated statin-induced changes in regulation of lipid metabolism and abundance of neutral lipid-containing cytoplasmic lipid droplets (LDs) in BC cells displaying different sensitivity to atorvastatin. Following atorvastatin treatment, accumulated LD levels inversely mirrored the marginal anti-proliferative effects in a dose and time-dependent manner in the less-sensitive BC cells. Transcriptional profiling excluded dysregulation of lipid uptake and efflux as specific mechanisms associated with differences in LD accumulation and anti-proliferative effects of atorvastatin. Notably, significant upregulation of genes involved in unsaturated fatty acid metabolism [stearoyl-CoA desaturase (SCD)] and cholesterol biosynthesis [3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)], were associated with atorvastatin insensitivity. Taken together, the increased ability to store neutral lipids in LDs as consequence of atorvastatin treatment likely confers a proliferative advantage to BC cells and may serve as potential biomarker of statin resistance in BC. Contributions of cholesterol biosynthesis and unsaturated fatty acid metabolism to LD formation should be thoroughly explored for better understanding of the molecular mechanisms underlying statin-induced effects against BC progression.
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影响因子：
5.2
作者：
Igal RA
通讯作者：
Igal RA
DOI：
10.1016/j.bbalip.2009.09.024
发表时间：
2010-03
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Li LO;Klett EL;Coleman RA
通讯作者：
Coleman RA
影响因子：
3.8
作者：
Garwood, Elisabeth R.;Kumar, Anjali S.;Baehner, Frederick L.;Moore, Dan H.;Au, Alfred;Hylton, Nola;Flowers, Chris I.;Garber, Judy;Lesnikoski, Beth-Ann;Hwang, E. Shelley;Olopade, Olofunmilao;Port, Elisa Rush;Campbell, Michael;Esserman, Laura J.
通讯作者：
Esserman, Laura J.
影响因子：
7.4
作者：
Feldt M;Bjarnadottir O;Kimbung S;Jirström K;Bendahl PO;Veerla S;Grabau D;Hedenfalk I;Borgquist S
通讯作者：
Borgquist S
影响因子：
45.3
作者：
Borgquist, Signe;Giobbie-Hurder, Anita;Thurlimann, Beat
通讯作者：
Thurlimann, Beat