Prolyl isomerase Pin1 binds to and stabilizes acetyl CoA carboxylase 1 protein, thereby supporting cancer cell proliferation
Prolyl isomerase Pin1 binds to and stabilizes acetyl CoA carboxylase 1 protein, thereby supporting cancer cell proliferation
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DOI：
10.18632/oncotarget.26691
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发表时间：
2019-02
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通讯作者：
K. Ueda;Yusuke Nakatsu;Takeshi Yamamotoya;Hiraku Ono;Yuki Inoue;Masa-Ki Inoue;Yu Mizuno;Y. Matsunaga;A. Kushiyama;H. Sakoda;M. Fujishiro;Shin-ichiro Takahashi;A. Matsubara;T. Asano
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文献类型：
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作者：
K. Ueda;Yusuke Nakatsu;Takeshi Yamamotoya;Hiraku Ono;Yuki Inoue;Masa-Ki Inoue;Yu Mizuno;Y. Matsunaga;A. Kushiyama;H. Sakoda;M. Fujishiro;Shin-ichiro Takahashi;A. Matsubara;T. Asano
据报道，脯氨酰异构酶Pin 1表达水平在大多数恶性组织中增加，并与不良结局相关。另一方面，脂肪生成的限速酶乙酰辅酶A羧化酶1（ACC 1）也在癌细胞中大量表达，以满足快速细胞增殖所需的脂肪酸（FA）的需求。我们发现Pin 1表达水平与人类前列腺癌中的ACC 1水平呈正相关，我们专注于Pin 1和ACC 1之间的关系。值得注意的是，已证明Pin 1在过表达系统中与ACC 1相关，但在前列腺癌细胞系DU 145中不与乙酰辅酶A羧化酶2（ACC 2）相关。这种关联由Pin 1中的WW结构域和ACC 1的C-末端结构域介导。有趣的是，Pin 1缺陷或Pin 1 siRNA或抑制剂胡桃醌治疗显着降低ACC 1蛋白表达，而不影响其mRNA水平，而Pin 1过表达增加ACC 1蛋白水平。此外，氯喹处理恢复了Pin 1 siRNA处理降低的ACC 1蛋白水平，表明Pin 1通过溶酶体途径抑制ACC 1降解。简而言之，我们得出结论，Pin 1导致ACC 1的稳定和增加。因此，Pin 1在癌细胞中的生长促进作用可能至少部分地由ACC 1蛋白的稳定性介导，这与Pin 1抑制剂作为抗癌药物的众所周知的潜力相对应。
The prolyl isomerase Pin1 expression level is reportedly increased in most malignant tissues and correlates with poor outcomes. On the other hand, acetyl CoA carboxylase 1 (ACC1), the rate limiting enzyme of lipogenesis is also abundantly expressed in cancer cells, to satisfy the demand for the fatty acids (FAs) needed for rapid cell proliferation. We found Pin1 expression levels to correlate positively with ACC1 levels in human prostate cancers, and we focused on the relationship between Pin1 and ACC1. Notably, it was demonstrated that Pin1 associates with ACC1 but not with acetyl CoA carboxylase 2 (ACC2) in the overexpression system as well as endogenously in the prostate cancer cell line DU145. This association is mediated by the WW domain in the Pin1 and C-terminal domains of ACC1. Interestingly, Pin1 deficiency or treatment with Pin1 siRNA or the inhibitor juglone markedly reduced ACC1 protein expression without affecting its mRNA level, while Pin1 overexpression increased the ACC1 protein level. In addition, chloroquine treatment restored the levels of ACC1 protein reduced by Pin1 siRNA treatment, indicating that Pin1 suppressed ACC1 degradation through the lysosomal pathway. In brief, we have concluded that Pin1 leads to the stabilization of and increases in ACC1. Therefore, it is likely that the growth-enhancing effect of Pin1 in cancer cells is mediated at least partially by the stabilization of ACC1 protein, corresponding to the well-known potential of Pin1 inhibitors as anti-cancer drugs.