Autophagy regulates lipolysis and cell survival through lipid droplet degradation in androgen-sensitive prostate cancer cells.
Autophagy regulates lipolysis and cell survival through lipid droplet degradation in androgen-sensitive prostate cancer cells.
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DOI：
10.1002/pros.22489
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发表时间：
2012-09-15
期刊：
影响因子：
2.8
通讯作者：
Hu, Chien-An A.
中科院分区：
文献类型：
--
作者：
Kaini, Ramesh R.;Sillerud, Laurel O.;Zhaorigetu, Siqin;Hu, Chien-An A.
雄激素剥夺疗法是前列腺癌（PCa）的标准治疗方法之一，可诱导雄激素反应性前列腺癌细胞凋亡和自噬。由于自噬可以促进细胞存活或死亡，因此了解其在前列腺癌治疗中的作用非常重要。本研究的目的是阐明自噬在雄激素敏感型前列腺癌细胞脂滴稳态和存活中的作用。在LNCaP和LAPC4细胞中使用木炭过滤血清或雄激素抑制剂casodex来产生雄激素剥夺。免疫荧光/共聚焦显微镜和免疫印迹分析监测自噬。3-甲基腺嘌呤、巴菲霉素A1或si- atg5抑制自噬后细胞内脂滴和三甘油酯水平分别通过油红O染色、三甘油酯脂肪酶测定和核磁共振三种独立的方法进行定量。雄激素剥夺诱导了两种雄激素敏感的PCa细胞系的自噬和脂滴的消耗，而通过药物或遗传手段阻断自噬抑制了脂滴的降解，从而抑制了脂肪分解和细胞生长。此外，在雄激素剥夺的情况下，LNCaP细胞中脂滴和自噬囊泡的共定位增加，通过阻断自噬通量可以进一步增强。雄激素剥夺过程中，自噬介导雄激素敏感PCa细胞的脂滴降解和脂解，有助于激素治疗过程中PCa细胞的存活。
Androgen deprivation therapy, one of the standard treatments for prostate cancer (PCa) induces apoptosis, as well as autophagy in androgen-responsive PCa cells. As autophagy can promote either cell survival or death, it is important to understand its role in PCa treatment. The objective of our study was to elucidate the function of autophagy in lipid droplet homeostasis and survival in androgen-sensitive PCa cells. To produce androgen deprivation, charcoal filtered serum or the androgen inhibitor casodex were used in LNCaP and LAPC4 cells. Autophagy was monitored by immunofluorescence/confocal microscopy and immunoblot analysis. Levels of intracellular lipid droplets and triacyglycerols after the inhibition of autophagy by 3-methyladenine, bafilomycin A1 orsi-ATG5 were quantified by three independent methods, Oil Red O staining, triacyglycerols lipase assay, and nuclear magnetic resonance. Androgen deprivation induced autophagy and the depletion of lipid droplets in both of the androgen-sensitive PCa cell lines examined, whereas the blockage of autophagy by pharmacological or genetic means inhibited lipid droplet degradation and therefore lipolysis and cell growth. In addition, under androgen deprivation, increased colocalization of lipid droplets and autophagic vesicles was observed in LNCaP cells, which can be further enhanced by blocking the autophagic flux. Autophagy mediates lipid droplet degradation and lipolysis in androgen-sensitive PCa cells during androgen deprivation which aids the survival of PCa cells during hormone therapy.
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