Radiosensitivity of colorectal cancer and radiation-induced gut damages are regulated by gasdermin E

• Published in: Cancer letters Vol. 529; pp. 1 - 10
• Main Authors: Tan, Gao, Lin, Chunjing, Huang, Chongyang, Chen, Bingxia, Chen, Jiaye, Shi, Yanqiang, Zhi, Fachao
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 31.03.2022; Elsevier Limited
• Subjects: Animals; Antibodies; Biomarkers, Tumor; Cancer therapies; Caspase 3 - metabolism; Caspase-3; Cell growth; Cell Line, Tumor; Chemotherapy; Cloning; Colitis - etiology; Colitis - metabolism; Colitis - pathology; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - complications; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - radiotherapy; CRISPR; Cytokines - metabolism; Disease Models, Animal; Drugs; Epithelial cells; Gasdermin E; Gastric cancer; Gastrointestinal Diseases - diagnosis; Gastrointestinal Diseases - etiology; Gastrointestinal Diseases - metabolism; Gene Expression; Humans; Immunohistochemistry; Intestine; Kaplan-Meier Estimate; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Killer Cells, Natural - pathology; Laboratory animals; Liver cancer; Lymphocyte Depletion; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Lymphocytes, Tumor-Infiltrating - pathology; Mice; Mice, Knockout; Pancreas; Pancreatic cancer; Patients; Plasmids; Pore Forming Cytotoxic Proteins - genetics; Pore Forming Cytotoxic Proteins - metabolism; Prognosis; Pyroptosis; Pyroptosis - genetics; Pyroptosis - radiation effects; Radiation Injuries - diagnosis; Radiation Injuries - etiology; Radiation Injuries - metabolism; Radiation therapy; Radiation Tolerance; Radiosensitivity; Radiotherapy; Radiotherapy - adverse effects; Radiotherapy - methods; Toxicity; Tumors; United States > US; Pyroptosis; Gasdermin E; Radiotherapy; Colorectal cancer
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2021.12.034

Although radiotherapy is an important clinical option available for colorectal cancer (CRC), its use is restricted due to low radiosensitivity of CRC and high toxicity to surrounding normal tissues. The purpose of this study is to investigate the molecular mechanism by which CRC is not sensitive to radiation and radiation causes toxicity to surrounding normal tissues. Here we found that GSDME was silenced in CRC but markedly expressed in their surrounding normal tissues. GSDME determines radiation-induced pyroptosis in CRC cells and normal epithelial cells through the caspase-3-dependent pathway. GSDME expression sensitizes radioresistant CRC cells to radiation. In the homograft model, after radiation treatment, the tumor volume and weight were significantly decreased in GSDME-expressed homograft tumors compared to GSDME-knockout homograft tumors. On the mechanism, radiation induced GSDME-mediated pyroptosis in CRC cells, which recruited and activated NK cells to enhance antitumor immunity. In addition, GSDME-knockout mice were protected from radiation-induced weight loss and tissue damages in the intestine, stomach, liver and pancreas compared to wild-type control littermates. In summary, we show that GSDME determines CRC radiosensitivity and radiation-related toxicity to surrounding normal tissues through caspase-3-dependent pyroptosis. Our finding reveals a previously unrecognized link between radiation and pyroptosis. •GSDME determines radiation-induced pyroptosis in intestinal epithelial cells (IECs) through the caspase-3-dependent pathway.•GSDME was silenced in CRC but markedly expressed in their adjacent non-tumor normal tissues, mainly in IECs. Increasing the expression of GSDME sensitizes radioresistant CRC cells and tumors.•GSDME expression enhanced the number of tumor-infiltrating NK lymphocytes that play an important role in radiation-induced anti-tumor immunity.•GSDME high-expressed in normal IECs contributes to radiotherapy-related gut damage through releasing pro-inflammatory cytokines.