Atorvastatin induces autophagy in prostate cancer PC3 cells through activation of LC3 transcription
Atorvastatin induces autophagy in prostate cancer PC3 cells through activation of LC3 transcription
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DOI：
10.4161/cbt.12.8.15978
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发表时间：
2011-10-15
影响因子：
3.6
通讯作者：
Yang, Wannian
中科院分区：
文献类型：
--
作者：
Toepfer, Nicholas;Childress, Chandra;Yang, Wannian
我们以前的研究已经证明阿托伐他汀通过抑制香叶基香叶的生物合成诱导雄激素受体阴性的前列腺癌PC3细胞的自噬(Parikh等人。前列腺癌2010；70：971-81)。本研究试图阐明阿托伐他汀诱导PC3细胞自噬的分子机制。用阿托伐他汀联合转录、蛋白翻译、PI-3激酶、mTOR和MAP激酶抑制剂处理PC3细胞。阿托伐他汀诱导的LC_3-II的升高可被翻译和转录抑制剂抑制，提示阿托伐他汀抑制香叶基香叶素的生物合成激活了LC_3的转录，从而导致LC_3-II的升高和自噬的激活。逆转录聚合酶链式反应和定量聚合酶链式反应分析表明，阿托伐他汀促进了香叶基香叶醇的表达，而香叶基香叶醇和阿托伐他汀的共同作用减弱了这种促进作用，证实了香叶基香叶醇抑制香叶基香叶基生物合成是导致香叶基香叶醇转录激活的原因。此外，我们发现MEK1/2抑制剂U0126和JNK抑制剂SP600125都能抑制阿托伐他汀诱导的Lc3-II的升高，提示阿托伐他汀对自噬的影响是通过ERK和JNK途径介导的。综上所述，阿托伐他汀通过激活LC3转录诱导前列腺癌PC3细胞自噬。
Our previous studies have demonstrated that atorvastatin induces autophagy in the androgen receptor negative prostate cancer PC3 cells through inhibition of geranylgeranyl biosynthesis (Parikh et al. Prostate 2010; 70:971-81). This study attempts to elucidate the molecular mechanism underlying atorvastatin-induced autophagy in PC3 cells. PC3 cells were treated with atorvastatin, in combination with the inhibitors for transcription, protein translation, PI-3 kinase, mTOR and MAP kinases. The atorvastatin-induced elevation of LC3-II was inhibited by both the translational and the transcriptional inhibitors, suggesting that the inhibition of geranylgeranyl biosynthesis by atorvastatin activates transcription of LC3, which results in elevation of LC3-II and activation of autophagy. RT-PCR and quantitative PCR assays showed that atorvastatin enhanced expression of LC3 mRNA, and addition of geranylgeraniol along with atorvastatin to the medium eliminated the enhancement, confirming the activation of transcription of LC3 is caused by atorvastatin-mediated inhibition of geranylgeranyl biosynthesis. Further, we found that both the MEK1/2 inhibitor U0126 and the JNK inhibitor SP600125, inhibited the atorvastatin-induced elevation of LC3-II, suggesting that the effect of atorvastatin on autophagy is mediated by the Erk and JNK pathways. Taken together, atorvastatin induces autophagy in prostate cancer PC3 cells through activation of LC3 transcription.