Inhibition of PTP1B blocks pancreatic cancer progression by targeting the PKM2/AMPK/mTOC1 pathway
Inhibition of PTP1B blocks pancreatic cancer progression by targeting the PKM2/AMPK/mTOC1 pathway
复制标题
抑制 PTP1B 通过靶向 PKM2/AMPK/mTOC1 通路来阻止胰腺癌进展
DOI：
10.1038/s41419-019-2073-4
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发表时间：
2019-11-19
影响因子：
9
通讯作者：
Shi, Dayong
中科院分区：
文献类型：
--
作者：
Xu, Qi;Wu, Ning;Shi, Dayong
胰腺癌是一种高度恶性的癌症，缺乏有效的治疗靶点。蛋白酪氨酸磷酸酶1B（PTP 1B）是糖尿病和肥胖症的有效治疗靶点，在肿瘤发生中也起着关键的积极或消极作用。然而，PTP 1B在胰腺癌中的作用仍然难以捉摸。在此，我们初步证明PTP 1B在胰腺肿瘤中高表达，并且与远处转移和肿瘤分期正相关，并且表明生存率低。然后，通过shRNA或通过特定的小分子抑制剂抑制PTP 1B在体外显著抑制胰腺癌细胞的生长、迁移和集落形成以及细胞周期停滞，并在体内抑制胰腺癌进展。机制研究表明，PTP 1B靶向PKM 2/AMPK/mTOC 1信号通路来调节细胞生长。PTP 1B抑制直接增加PKM 2 Tyr-105磷酸化，进一步导致AMPK的显著活化，从而降低mTOC 1活性并导致p70 S6 K抑制。同时，PKM 2活性降低导致PRAS 40磷酸化水平降低也有助于抑制mTOC 1。总的来说，这些发现支持PTP 1B作为癌基因和PDAC的有希望的治疗靶点的概念。
Pancreatic cancer is a highly malignant cancer and lacks effective therapeutic targets. Protein-tyrosine phosphatase 1B (PTP1B), a validated therapeutic target for diabetes and obesity, also plays a critical positive or negative role in tumorigenesis. However, the role of PTP1B in pancreatic cancer remains elusive. Here, we initially demonstrated that PTP1B was highly expressed in pancreatic tumors, and was positively correlated with distant metastasis and tumor staging, and indicated poor survival. Then, inhibition of PTP1B either by shRNA or by a specific small-molecule inhibitor significantly suppressed pancreatic cancer cell growth, migration and colony formation with cell cycle arrest in vitro and inhibited pancreatic cancer progression in vivo. Mechanism studies revealed that PTP1B targeted the PKM2/AMPK/mTOC1 signaling pathway to regulate cell growth. PTP1B inhibition directly increased PKM2 Tyr-105 phosphorylation to further result in significant activation of AMPK, which decreased mTOC1 activity and led to inhibition of p70S6K. Meanwhile, the decreased phosphorylation of PRAS40 caused by decreased PKM2 activity also helped to inhibit mTOC1. Collectively, these findings support the notion of PTP1B as an oncogene and a promising therapeutic target for PDAC.