Dou Zhihui, Zhang Xuetian, Su Wei, Zhang Taotao, Ye Fei, Zhao Dapeng, Chen Xiaohua, Li Qiang, Zhang Hong, Di Cuixia
Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences Lanzhou 730000, Gansu, China.
Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences Lanzhou 730000, Gansu, China.
Am J Cancer Res. 2023 Jul 15;13(7):2922-2937. eCollection 2023.
Indisulam is a synthetic sulfonamides drug with anticancer activity in various tumors. However, the effect and molecular mechanism of indisulam have still not been studied in human cervical cancer. We treated human cervical cancer cell lines (HeLa and C33A) with indisulam, evaluated its efficacy, and investigated its molecular targets. Indisulam inhibited tumor growth and induced RBM39 degradation in a dose-dependent manner. RNA-seq and proteomics analysis revealed that indisulam disrupted transcriptional regulation pathways related to mRNA splicing and apoptosis. More importantly, indisulam caused mis-splicing of RNA transcripts including p73 isoforms ΔNp73 and TAp73 which have opposite roles in apoptosis regulation. Indisulam increased TAp73 expression and triggered mitochondrial apoptosis independent of p53 status in HeLa cells. In summary, our data suggests that indisulam has therapeutic potential in cervical cancer, representing an attractive strategy in p53-disrupted cancers and should be further investigated.
因迪舒仑是一种在多种肿瘤中具有抗癌活性的合成磺胺类药物。然而，因迪舒仑在人宫颈癌中的作用及分子机制尚未得到研究。我们用因迪舒仑处理人宫颈癌细胞系（HeLa和C33A），评估其疗效，并研究其分子靶点。因迪舒仑以剂量依赖的方式抑制肿瘤生长并诱导RBM39降解。RNA测序和蛋白质组学分析表明，因迪舒仑破坏了与mRNA剪接和凋亡相关的转录调控途径。更重要的是，因迪舒仑导致RNA转录本的错误剪接，包括在凋亡调控中具有相反作用的p73异构体ΔNp73和TAp73。因迪舒仑增加TAp73表达并在HeLa细胞中触发不依赖于p53状态的线粒体凋亡。总之，我们的数据表明因迪舒仑在宫颈癌中具有治疗潜力，是p53功能失调癌症中的一种有吸引力的策略，应进一步研究。
