Targeting PRKACA inhibits proliferation and sensitizes glioma cells to temozolomide via pyroptosis pathway

Abstract Temozolomide is a major chemotherapeutic agent in the clinical treatment of gliomas. Unfortunately, patients usually develop drug resistance. Pyroptosis is recently considered as a new type of programmed cell death, however, the effect and mechanism of the pyroptosis pathway in glioma are unclarified. Gene expression profiles were obtained from the public databases. A total of 37 differentially expressed genes related to pyroptosis were identified, and the molecular subgroups were prognostically different. A risk-score model of 11 pyroptosis-related genes was constructed and effectively classified glioma patients into high- and low-risk groups, which were significantly distinct in prognosis and immune cell infiltration. PRKACA was differentially expressed in 20 of 33 cancer types. The expression was also associated with tumor stage and prognosis. In addition, PRKACA was active and correlated with immune markers. Experimentally, PRKACA knockdown inhibited the malignant phenotypes and induced pyroptosis, as well as sensitized glioma cells to TMZ. In conclusions, a risk-score model was constructed to perform risk classification and prognostic prediction for glioma patients. Moreover, PAKACA was identified as a promising therapeutic candidate for treating patients who are resistant or less responsive to TMZ.