<br>抑制 PTP1B 通过靶向 PKM2/AMPK/mTOC1 通路来阻止胰腺癌的进展。,Cell Death & Disease

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抑制 PTP1B 通过靶向 PKM2/AMPK/mTOC1 通路来阻止胰腺癌的进展。
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-11-19 , DOI: 10.1038/s41419-019-2073-4
Qi Xu _{1,

2,

3} , Ning Wu _{1,

2} , Xiangqian Li _{3,

4} , Chuanlong Guo _{1,

2,

3} , Chao Li _{1,

2,

3} , Bo Jiang _{1,

2} , Huaizhi Wang ₅ , Dayong Shi _{2,

3,

4}

Affiliation

胰腺癌是一种恶性程度很高的癌症，缺乏有效的治疗靶点。蛋白酪氨酸磷酸酶 1B (PTP1B) 是糖尿病和肥胖症的有效治疗靶点，在肿瘤发生中也发挥着关键的积极或消极作用。然而，PTP1B 在胰腺癌中的作用仍然难以捉摸。在这里，我们初步证明PTP1B在胰腺肿瘤中高表达，并且与远处转移和肿瘤分期呈正相关，并表明生存率较差。然后，通过 shRNA 或特定小分子抑制剂抑制 PTP1B 可显着抑制胰腺癌细胞的生长、迁移和集落形成，并在体外抑制细胞周期，并在体内抑制胰腺癌进展。机制研究表明，PTP1B靶向PKM2/AMPK/mTOC1信号通路来调节细胞生长。 PTP1B 抑制直接增加 PKM2 Tyr-105 磷酸化，进一步导致 AMPK 显着激活，从而降低 mTOC1 活性并导致 p70S6K 抑制。同时，PKM2活性降低导致PRAS40磷酸化降低也有助于抑制mTOC1。总的来说，这些发现支持 PTP1B 作为癌基因和有希望的 PDAC 治疗靶点的概念。

"点击查看英文标题和摘要"

Inhibition of PTP1B blocks pancreatic cancer progression by targeting the PKM2/AMPK/mTOC1 pathway.

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.

更新日期：2019-11-19

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