CRTAC1 Enhances the Chemosensitivity of Non-Small Cell Lung Cancer to Cisplatin Via Regulating Ca ²/NFAT/STUB1/Akt1 Axis Induced-Apoptosis

Background: Cisplatin-based dualagent chemotherapy is the preferred first-line chemotherapy for non-small cell lung cancer (NSCLC) patients. Moreover, the sensitivity of patients to cisplatin is associated with good prognosis, so it is very important to find biomarkers to predict the sensitivity of cisplatin, which can effectively improve the efficacy of cisplatin chemotherapy.<br><br>Methods: GEO dataset was used to analyze the relationship between CRTAC1 expression and overall survival in NSCLC patients treated with cisplatin. The effect of CRTAC1 on cisplatin sensitivity of NSCLC cell lines in vitro and in vivo was evaluated by ATP assay, flow cytometry and animal experiments. Proteomics, quantitative real-time PCR (qRT‐PCR), western blotting, dual luciferase reporter and loss-of-function experiments were applied to explore the molecular mechanism of CRTAC1 enhancing cisplatin sensitivity.<br><br>Findings: High CRTAC1 expression was positively associated with the prognosis of NSCLC patients treated with cisplatin. In vitro and in vivo functional experiments showed that CRTAC1 can significantly improve the sensitivity of NSCLC cells to cisplatin. CRTAC1 increased the intracellular Ca²⁺ level of NSCLC cells treated by cisplatin, enhanced the transcription activity of NFAT, thereby promoting the expression of STUB1 protein and accelerating the degradation rate of Akt1 protein, and then enhances cisplatin-induced apoptosis by inhibiting PI3K/Akt signaling pathway.<br><br>Interpretation: CRTAC1 overexpression increases the chemosensitivity of NSCLC to cisplatin treatment by inducing Ca²⁺-dependent Akt1 degradation and apoptosis, suggesting the potential of CRTAC1 as a biomarker for predicting cisplatin chemosensitivity. Our results further reveal that modulating the expression of CRTAC1 could be a new strategy for increasing the efficacy of cisplatin in chemotherapy of NSCLC patients.<br><br>Funding Information: This work was supported by the National Natural Science Foundation of China (NSFC81872587); Wenzhou Science &amp; Technology Bureau (ZY2019004); Zhejiang Provincial Natural Science Foundation of China (LQ22H260006); Key Project of Science and Technology Innovation Team of Zhejiang Province (2013TD10) and Key Discipline of Zhejiang Province in Medical Technology (First Class, Category A).<br><br>Declaration of Interests: The authors declare that they have no competing interests.<br><br>Ethics Approval Statement: The subcutaneous tumorigenesis experiments in nude mice in this study were in line with the management regulations of the Experimental Animal Ethics Committee of Wenzhou Medical University. Animal experiments were performed at the animal institute of Wenzhou Medical University according to protocols approved by the Laboratory Animal Center of Wenzhou Medical University and the Laboratory Animal Ethics Committee of Wenzhou Medical University.