Peroxisome proliferator-activated receptor-gamma protects ERBB2-positive breast cancer cells from palmitate toxicity.
Peroxisome proliferator-activated receptor-gamma protects ERBB2-positive breast cancer cells from palmitate toxicity.
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DOI：
10.1186/bcr2240
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Conklin DS
中科院分区：
文献类型：
--
作者：
Kourtidis A;Srinivasaiah R;Carkner RD;Brosnan MJ;Conklin DS
脂肪酸和中性脂在非脂肪组织中的积累具有细胞毒性。我们最近发现，ERBB2阳性的乳腺癌细胞产生大量的脂肪，这是由于过氧体增殖物激活受体γ结合蛋白和核受体NR1d1(核受体亚家族1，D组，成员1；REV-ERBα)的过度表达。这些基因上调了新生脂肪酸的合成，这是这些细胞产生能量和生存的关键途径。NR1D1和PPARγ结合蛋白在功能上与PPARγ相关，PPAR是一种成熟的脂肪生成和脂肪储存的正向调节因子。研究GW9662和外源性棕榈酸酯对乳腺细胞(BT474、MDA-MB-361、MCF-7和人乳腺上皮细胞)单层培养的影响。采用脂肪酸的质谱定量和细胞生长、细胞凋亡、甘油三酯储存和活性氧产生的高含量荧光显微镜分析。ERBB2阳性的乳腺癌细胞对拮抗剂GW9662抑制PPARγ活性更为敏感。抑制PPARγ会导致细胞内总脂肪水平的增加，主要是因为棕榈酸和硬脂酸不饱和酸的增加。外源性棕榈酸酯对ERBB2阳性细胞有致死作用，对ERBB2阴性细胞无致死作用。GW9662可加重棕榈酸酯对BT474和MDA-MB-361细胞的影响，但对MCF-7和人乳腺上皮细胞无明显影响。与ERBB2阳性细胞相比，给药后ERBB2阴性细胞的脂肪储存增加了五到十倍，这表明ERBB2阳性细胞最大限度地发挥了储存脂肪的能力，额外的棕榈酸酯对这些细胞是有毒的。PPARγ抑制和棕榈酸酯给药均导致BT474细胞产生更多的活性氧。这种治疗导致的细胞死亡可以被抗氧化剂N-乙酰半胱氨酸所抵消。我们的发现表明，PPARγ的活性使ERBB2阳性的乳腺癌细胞能够将脂肪酸转化为甘油三酯，从而避免了脂肪毒性导致的细胞死亡。内源性棕榈酸酯毒性代表了ERBB2阳性乳腺癌的一种遗传特性，可用于治疗干预。
Accumulation of fatty acids and neutral lipids in nonadipose tissues is cytotoxic. We recently showed that ERBB2-positive breast cancer cells produce significantly high amounts of fats, because of overexpression of the peroxisome proliferator-activated receptor (PPAR)γ-binding protein and the nuclear receptor NR1D1 (nuclear receptor subfamily 1, group D, member 1; Rev-erbα). These genes upregulate de novo fatty acid synthesis, which is a critical pathway for the energy production and survival of these cells. NR1D1 and PPARγ-binding protein are functionally related to PPARγ, a well established positive regulator of adipogenesis and lipid storage. The effects of GW9662 and exogenously added palmitate on breast cells (BT474, MDA-MB-361, MCF-7, and human mammary epithelial cells) in monolayer culture were assessed. Mass spectrometric quantitation of fatty acids and fluorescence-based high content microscopy assays of cell growth, apoptosis, triglyceride storage and reactive oxygen species production were used. ERBB2-positive breast cancer cells are more sensitive to inhibition of PPARγ activity by the antagonist GW9662. PPARγ inhibition results in increased levels of total fats in the cells, mostly because of increased amounts of palmitic and stearic unsaturated acids. Administration of exogenous palmitate is lethal to ERBB2-positive but not to ERBB2-negative cells. GW9662 exacerbates the effects of palmitate addition on BT474 and MDA-MB-361 cells, but it has no significant effect on MCF-7 and human mammary epithelial cells. Palmitate administration results in a fivefold to tenfold greater increase in fat stores in ERBB2-negative cells compared with ERBB2-positive cells, which suggests that the ERBB2-positive cells have maximized their ability to store fats and that additional palmitate is toxic to these cells. Both PPARγ inhibition and palmitate administration result in increased reactive oxygen species production in BT474 cells. The cell death that results from this treatment can be counteracted by the antioxidant N-acetyl cysteine. Our findings indicate that PPARγ activity enables ERBB2-positive breast cancer cells, which produce high levels of fat, to convert fatty acids to triglycerides, allowing these cells to avert the cell death that results from lipotoxicity. Endogenous palmitate toxicity represents a genetically based property of ERBB2-positive breast cancer that can be exploited for therapeutic intervention.
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影响因子：
4.7
作者：
Menendez, JA;Colomer, R;Lupu, R
通讯作者：
Lupu, R
影响因子：
4.8
作者：
Shimabukuro, M;Higa, M;Unger, RH
通讯作者：
Unger, RH
影响因子：
4.8
作者：
Listenberger, LL;Ory, DS;Schaffer, JE
通讯作者：
Schaffer, JE
DOI：
10.1073/pnas.0403390101
发表时间：
2004-07-20
影响因子：
11.1
作者：
Menendez, JA;Vellon, L;Lupu, R
通讯作者：
Lupu, R
影响因子：
4.8
作者：
Fontaine, C;Dubois, G;Staels, B
通讯作者：
Staels, B