Ueda Koji, Nakatsu Yusuke, Yamamotoya Takeshi, Ono Hiraku, Inoue Yuki, Inoue Masa-Ki, Mizuno Yu, Matsunaga Yasuka, Kushiyama Akifumi, Sakoda Hideyuki, Fujishiro Midori, Takahashi Shin-Ichiro, Matsubara Akio, Asano Tomoichiro
Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima City, Hiroshima, Japan.
Department of Clinical Cell Biology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba City, Japan.
Oncotarget. 2019 Feb 26;10(17):1637-1648. doi: 10.18632/oncotarget.26691.
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.
据报道，脯氨酰异构酶Pin1在大多数恶性组织中的表达水平升高，且与不良预后相关。另一方面，脂肪生成的限速酶乙酰辅酶A羧化酶1（ACC1）在癌细胞中也大量表达，以满足快速细胞增殖所需的脂肪酸（FAs）需求。我们发现Pin1在人前列腺癌中的表达水平与ACC1水平呈正相关，于是我们重点研究了Pin1与ACC1之间的关系。值得注意的是，在过表达系统以及前列腺癌细胞系DU145内源性表达中均证实，Pin1与ACC1相互作用，而不与乙酰辅酶A羧化酶2（ACC2）相互作用。这种相互作用是由Pin1中的WW结构域和ACC1的C末端结构域介导的。有趣的是，Pin1缺陷或用Pin1 siRNA或抑制剂胡桃醌处理可显著降低ACC1蛋白表达，而不影响其mRNA水平，而Pin1过表达则增加ACC1蛋白水平。此外，氯喹处理可恢复Pin1 siRNA处理降低的ACC1蛋白水平，表明Pin1通过溶酶体途径抑制ACC1降解。简而言之，我们得出结论，Pin1可导致ACC1的稳定并增加其表达。因此，Pin1在癌细胞中的促生长作用可能至少部分是由ACC1蛋白的稳定介导的，这与Pin1抑制剂作为抗癌药物的众所周知的潜力相一致。
