Metformin exerts anti-AR-negative prostate cancer activity via AMPK/autophagy signaling pathway.
Metformin exerts anti-AR-negative prostate cancer activity via AMPK/autophagy signaling pathway.
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二甲双胍通过 AMPK/自噬信号通路发挥抗 AR 阴性前列腺癌活性
DOI：
10.1186/s12935-021-02043-2
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发表时间：
2021-08-17
影响因子：
5.8
通讯作者：
Hou J
中科院分区：
文献类型：
--
作者：
Chen C;Wang H;Geng X;Zhang D;Zhu Z;Zhang G;Hou J
在开发有效的前列腺癌治疗策略的目标的鼓舞下，本研究探索了二甲双胍介导的AR阴性前列腺癌抑制作用的机制。采用CCK-8试验、集落形成试验和划痕试验检测DU-145和PC-3细胞的细胞行为。流式细胞仪检测细胞周期分布。用二甲双胍诱导细胞自噬，并使用自噬抑制剂3-MA评估自噬水平。通过免疫荧光检测LC 3B以确定自噬水平。Western blot检测细胞增殖、自噬和细胞周期。用靶向AMPK-α1和AMPK-α2的AMPK siRNA转染DU 145和PC 3细胞系。采用体内成瘤实验评价二甲双胍的抗前列腺癌作用。本研究证实了二甲双胍对前列腺癌细胞株增殖的抑制作用，其机制与自噬和细胞周期阻滞于G 0/G1期有关。Metalloy还诱导AMPK活化，显著促进LC 3 II表达，并下调p62/SQSTM 1表达。动物实验显示，二甲双胍组肿瘤体积较小，同时p-AMPK（Thr 172）、LC 3B水平上调，Ki-67水平下调，生化指标未见异常。这项研究发现，自噬诱导可能是二甲双胍抑制AR阴性前列腺癌生长的机制。此外，AMPK/自噬通路的激活可能是未来治疗AR阴性前列腺癌的有效方法。
Encouraged by the goal of developing an effective treatment strategy for prostate cancer, this study explored the mechanism involved in metformin-mediated inhibition of AR-negative prostate cancer. Cell behaviors of DU145 and PC3 cells were determined by CCK8 test, colony formation experiment and scratch test. Flow cytometry was used to detect cell cycle distribution. Cell autophagy was induced with metformin, and an autophagy inhibitor, 3-MA, was used to assess the level of autophagy. Detection of LC3B by immunofluorescence was conducted to determine autophagy level. Cell proliferation, autophagy and cell cycle were examined by performing Western blot. DU145 and PC3 cell lines were transfected with AMPK siRNA targeting AMPK-α1 and AMPK-α2. Tumor formation experiment was carried out to evaluate the anti-prostate cancer effect of metformin in vivo. The inhibitory effect of metformin on the proliferation of prostate cancer cell lines was confirmed in this study, and the mechanism of such an effect was related to autophagy and the block of cell cycle at G0/G1 phase. Metformin also induced the activation of AMPK, markedly promoted expression of LC3II, and down-regulated the expression of p62/SQSTM1. Animal experiments showed that the tumor volume of metformin group was smaller, meanwhile, the levels of p-AMPK (Thr172) and LC3B were up-regulated and the Ki-67 level was down-regulated, without abnormalities in biochemical indicators. This study found that autophagy induction might be the mechanism through which metformin suppressed the growth of AR-negative prostate cancer. Moreover, the activation of AMPK/autophagy pathway might be a therapeutically effective for treating AR-negative prostate cancer in the future.
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影响因子：
5
作者：
Pennanen, Pasi;Syvala, Heimo;Murtola, Teemu J.
通讯作者：
Murtola, Teemu J.
影响因子：
3.8
作者：
Jagadish N;Parashar D;Gupta N;Agarwal S;Suri V;Kumar R;Suri V;Sadasukhi TC;Gupta A;Ansari AS;Lohiya NK;Suri A
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作者：
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通讯作者：
Mucci, Lorelei A.
影响因子：
4.8
作者：
Joshua, A. M.;Zannella, V. E.;Pollak, M.
通讯作者：
Pollak, M.
影响因子：
9
作者：
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