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  3. SGLT2 promotes pancreatic cancer progression by activating the Hippo signaling pathway via the hnRNPK-YAP1 axis

SGLT2 promotes pancreatic cancer progression by activating the Hippo signaling pathway via the hnRNPK-YAP1 axis

  • Cancer Lett. 2021 Oct 28;519:277-288. doi: 10.1016/j.canlet.2021.07.035.
Dianyun Ren 1,  Yan Sun 2,  Dan Zhang 3,  Dan Li 4,  Zhiqiang Liu 5,  Xin Jin 6,  Heshui Wu 7
Affiliations

Affiliations

  • 1 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address: rendianyun@hust.edu.cn.
  • 2 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address: yansun@hust.edu.cn.
  • 3 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address: whuh_zd@163.com.
  • 4 Cardiovascular Medicine Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address: 547039279@qq.com.
  • 5 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address: drliuzq@hust.edu.cn.
  • 6 Department of Urology, The Second Xiangya Hospital, Central South University, Changsha,Hunan, 410011, China. Electronic address: jinxinxy2@csu.edu.cn.
  • 7 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address: heshuiwu@hust.edu.cn.
PMID: 34314754 DOI: 10.1016/j.canlet.2021.07.035
Abstract

SGLT2 is overexpressed in various cancers, including pancreatic Cancer. However, the mechanisms underlying the tumorigenic effects of SGLT2 in pancreatic Cancer remain unclear. In this study, we demonstrated that SGLT2 inhibition significantly suppressed the growth of pancreatic Cancer cells in vitro and in vivo. RNA Sequencing, Real-Time PCR, and Western blot analyses revealed that SGLT2 silencing or inhibition suppressed Hippo signaling activation by downregulating YAP1 expression. Liquid chromatography-mass spectrometry and immunoprecipitation analyses showed that SGLT2 interacted with hnRNPK, promoting its nuclear translocation and thereby enhancing hnRNPK-induced YAP1 transcription. Importantly, YAP1 inhibitor enhanced the anti-pancreatic Cancer effect of SGLT2 Inhibitor in mice bearing pancreatic tumors. These findings suggest that SGLT2 promotes pancreatic Cancer progression by activating the Hippo signaling pathway through the hnRNPK-YAP1 axis. Hence, SGLT2 inhibition alone or combined with YAP1 inhibition may represent a promising therapeutic approach for pancreatic Cancer.

Keywords

Hippo signaling pathway; Pancreatic cancer; SGLT2 inhibitor; YAP1 inhibitor.

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Products
  • Cat. No.
    Product Name
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  • HY-P1727
    99.89%, YAP Antagonist
    YAP