Gsdmc-KO Mouse

Gsdmc, or gasdermin C, is a member of the gasdermin family. Pyroptosis, a form of regulated cell death, is mediated by gasdermin family members, and Gsdmc is involved in a caspase-8-mediated pyroptotic pathway. For example, the metabolite α-ketoglutarate (α-KG) can induce pyroptosis through caspase-8-mediated cleavage of Gsdmc [1]. It is also associated with various disease-related processes such as tumor growth and metastasis, and pancreatic adenocarcinoma progression [1,2].

In pancreatic adenocarcinoma, depletion of Gsdmc inhibits the proliferation, invasion, and migration of pancreatic adenocarcinoma cells, suggesting Gsdmc may promote the proliferation and migration of these cell lines [2]. In breast cancer, antibiotic chemotherapy drugs can induce pyroptosis through the Gsdmc/caspase-8 non-canonical pyroptosis pathway, leading to tumour necrosis [3]. Additionally, Gsdmc can sensitize tumor cells to PARP inhibitor therapy, promoting tumor clearance independent of BRCA deficiency in multiple cancer types. Gsdmc-mediated cancer cell pyroptosis enhances the killing of tumor cells by PARPi and increases memory CD8+ T cell population, promoting cytotoxic CD8+ T cell infiltration in the tumor microenvironment [4].

In conclusion, Gsdmc is significantly involved in pyroptosis-related biological functions, especially in the context of tumor-related diseases. Studies using gene-knockout or conditional-knockout mouse models, though not directly detailed in the provided references, would likely further elucidate its role in these disease processes. These findings offer potential new therapeutic targets for treating diseases such as pancreatic adenocarcinoma and breast cancer where Gsdmc plays a part in promoting tumor-related phenotypes [2,3,4].

References:

1. Zhang, Jia-Yuan, Zhou, Bo, Sun, Ru-Yue, Chen, Hang-Zi, Wu, Qiao. 2021. The metabolite α-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8. In Cell research, 31, 980-997. doi:10.1038/s41422-021-00506-9. https://pubmed.ncbi.nlm.nih.gov/34012073/

2. Yan, Cheng, Niu, Yandie, Li, Feng, Zhao, Wei, Ma, Liukai. 2022. System analysis based on the pyroptosis-related genes identifies GSDMC as a novel therapy target for pancreatic adenocarcinoma. In Journal of translational medicine, 20, 455. doi:10.1186/s12967-022-03632-z. https://pubmed.ncbi.nlm.nih.gov/36199146/

3. Hou, Junwei, Zhao, Rongce, Xia, Weiya, Tainer, John A, Hung, Mien-Chie. 2020. PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis. In Nature cell biology, 22, 1264-1275. doi:10.1038/s41556-020-0575-z. https://pubmed.ncbi.nlm.nih.gov/32929201/

4. Wang, Shuanglian, Chang, Chiung-Wen, Huang, Juan, Hung, Mien-Chie, Hou, Junwei. 2024. Gasdermin C sensitizes tumor cells to PARP inhibitor therapy in cancer models. In The Journal of clinical investigation, 134, . doi:10.1172/JCI166841. https://pubmed.ncbi.nlm.nih.gov/37883181/