2. Academic Validation
  3. Nuclear translocation of Gasdermin D sensitizes colorectal cancer to chemotherapy in a pyroptosis-independent manner

Nuclear translocation of Gasdermin D sensitizes colorectal cancer to chemotherapy in a pyroptosis-independent manner

  • Oncogene. 2022 Oct 16. doi: 10.1038/s41388-022-02503-7.
Xiao Peng # 1,  Risi Na # 2,  Wenting Zhou 2,  Xiaole Meng 2,  Yunhai Yang 3,  Shohreh Amini 4,  Liwei Song 5
Affiliations

Affiliations

  • 1 Department of Biology, Temple University, BioLife Building, 1900 North 12th Street, Philadelphia, PA, 19122-6078, USA.
  • 2 Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, 2000 Xiang'an East Road, Xiamen, 361102, China.
  • 3 Department of Oncological Surgery, Shanghai Chest Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 241 West Huaihai Road, Xuhui District, Shanghai, 200030, China. yangyunhai_oncobio@shchest.org.
  • 4 Department of Biology, Temple University, BioLife Building, 1900 North 12th Street, Philadelphia, PA, 19122-6078, USA. shohreh.amini@temple.edu.
  • 5 Department of Oncological Surgery, Shanghai Chest Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 241 West Huaihai Road, Xuhui District, Shanghai, 200030, China. songliwei_chest@shchest.org.
  • # Contributed equally.
PMID: 36245058 DOI: 10.1038/s41388-022-02503-7
Abstract

Gasdermin D (GSDMD) has recently been identified as a cytoplasmic effector protein that plays a central role in Pyroptosis of immune cells. However, GSDMD is a universally expressed protein, and its function beyond Pyroptosis, especially in Cancer cells, has not been well characterized. Here, we report that predominant localization of GSDMD in the nucleoplasm in vivo indicates favorable clinical outcomes in colorectal Cancer, while a lack of nuclear localization of GSDMD is associated with poor outcomes. Nuclear GSDMD, rather than cytoplasmic GSDMD, inhibits cell growth and promotes Apoptosis in colorectal Cancer. Hypoxia in the tumor microenvironment accounts for mild or moderate nuclear translocation of GSDMD in vivo. Under the stimulation of chemotherapy drugs, nuclear GSDMD promotes Apoptosis via regulation of its subcellular distribution rather than pyroptosis-related cleavage. After nuclear translocation, GSDMD interacts with PARP-1 to dramatically inhibit its DNA damage repair-related function by functioning like the PARP Inhibitor olaparib, thus forming a "hypoxia/chemotherapy-GSDMD nuclear translocation-PARP-1 blockade-DNA damage and apoptosis" axis. This study redefines the pyroptosis-independent function of GSDMD and suggests that the subcellular localization of GSDMD may serve as a molecular indicator of clinical outcomes and a promising therapeutic target in colorectal Cancer.

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