A PLK1 kinase inhibitor enhances the chemosensitivity of cisplatin by inducing pyroptosis in oesophageal squamous cell carcinoma

Abstract

Background Targeting PLK1 has recently been proven as a viable therapeutic strategy against oesophageal squamous cell carcinom (ESCC). Therefore, this study aimed to explore whether the PLK1 inhibitor BI2536 is able to sensitize ESCC cells to cisplatin (DDP) and determine the underlying mechanisms. Methods Viability, clonogenicity, cell cycle distribution and apoptosis were assessed in ESCC cells treated with BI2536 or DDP alone or in combination. Checkpoint activation was examined by immunoblotting and immunohistochemistry. Xenograft model was used to assess the efficacy of the co-treatment. The expression level of GSDME in tissue samples were examined by immunohistochemistry. Findings We found that the combination of BI2536 and DDP was synergistic in ESCC cells, which induced pyroptosis in ESCC cells at low doses. Mechanistic studies revealed that BI2536 significantly induced DNA damage and impaired the DNA damage repair pathway in DDP-treated cells both in vitro and in vivo . Interestingly, we found that co-treatment with BI2536 and DDP induced pyroptosis in ESCC cells depending on the caspase-3/GSDME pathway. Importantly, our study found that GSDME was more highly expressed in tumour tissue than that in normal adjacent tissues, and could serve as a prognostic factor. Interpretation BI2536 sensitizes ESCC cells to DDP by inhibiting the DNA damage repair pathway and inducing pyroptosis, which provides new information for understanding pyroptosis. Our study also reveals that the PLK1 inhibitor BI2536 may be an attractive candidate for ESCC targeted therapy, especially when combined with DDP for treating the GSDME overexpression subtype. Fund National 973 Program and National Natural Science Fundation of China.

The role of pyroptosis in cancer: pro-cancer or pro-“host”?

“…The application of a caspase-1 inhibitor can interfere with the expression of NLRP3 and block the production of IL-1β and IL-18 and the release of LDH induced by LPS 103 . In addition, the level of GSDME was more highly in esophageal squamous cell carcinoma (ESCC) than in normal adjacent tissues 104 . miR-214 suppresses cell growth and metastasis by modulating caspase-1-mediated cell pyroptosis in glioma cells 105 .…”

The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer

“…Due to progressive dysphagia, esophageal stenosis, and high resistance to radiotherapy and chemotherapy, it often lost good efficacy 54 . Studies have found that the use of BI2536 which is an ATP-binding domain inhibitor of Polo-like kinase-1 (PLK1), in combination with Cisplatin on esophageal cancer cells can enhance the activity of caspase-3, cause pyroptosis, and in parallel to enhance DNA damage 55 . In addition, Tang et al found that Metformin, a drug widely used in type 2 diabetes, could reduce the expression of Pyruvate kinase isozyme type M2 (PKM2) in esophageal cancer cells.…”

Mechanisms and Therapeutic Regulation of Pyroptosis in Inflammatory Diseases and Cancer

“…For example, a polo-like Kinase 1 (PLK1) inhibitor could sensitize esophageal squamous cell carcinoma (ESCC) cells to cisplatin by inhibiting the DNA damage repair pathway and inducing Bax/caspase3/GSDME pathway-mediated pyroptosis. The new information indicates that PLK1 inhibitor may be an attractive candidate for ESCC targeted therapy, especially when combined with cisplatin for treating GSDME-overexpressing tumors [77]. In a recent study, Fan et al developed a strategy to combine decitabine (DAC) with chemotherapy nanomedicines, triggering tumor cell pyrolysis through epigenetics, thereby further enhancing the immunological effects of chemotherapy.…”