Xiu Wenhao, Zhang Yujia, Tang Dongfang, Lee Sau Har, Zeng Rui, Ye Tingjie, Li Hua, Lu Yanlin, Qin Changtai, Yang Yuxi, Yan Xiaofeng, Wang Xiaoling, Hu Xudong, Chu Maoquan, Sun Zhumei, Xu Wei
School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Department of Clinical Medicine, Suzhou Vocational Health College, Suzhou, Jiangsu, China.
Cell Oncol (Dordr). 2024 Dec;47(6):2201-2215. doi: 10.1007/s13402-024-00999-7. Epub 2024 Oct 7.
Taxol is the first-line chemo-drug for advanced non-small cell lung cancer (NSCLC), but it frequently causes acquired resistance, which leads to the failure of treatment. Therefore, it is critical to screen and characterize the mechanism of the taxol-resistance reversal agent that could re-sensitize the resistant cancer cells to chemo-drug.
The cell viability, sphere-forming and xenografts assay were used to evaluate the ability of ASIV to reverse taxol-resistance. Immunohistochemistry, cytokine application, small-interfering RNA, small molecule inhibitors, and RNA-seq approaches were applied to characterize the molecular mechanism of inhibition of epiregulin (EREG) and downstream signaling by ASIV to reverse taxol-resistance.
ASIV reversed taxol resistance through suppression of the stemness-associated genes of spheres in NSCLC. The mechanism exploration revealed that ASIV promoted the K48-linked polyubiquitination of EREG along with degradation. Moreover, EREG could be triggered by chemo-drug treatment. Consequently, EREG bound to the ErbB receptor and activated the ERK signal to regulate the expression of the stemness-associated genes. Inhibition of EREG/ErbB/ERK could reverse the taxol-resistance by inhibiting the stemness-associated genes. Finally, it was observed that TGFβ and Hedgehog signaling were downstream of EREG/ErbB/ERK, which could be targeted using inhibitors to reverse the taxol resistance of NSCLC.
These findings revealed that inhibition of EREG by ASIV reversed taxol-resistance through suppression of the stemness of NSCLC via EREG/ErbB/ERK-TGFβ, Hedgehog axis.
紫杉醇是晚期非小细胞肺癌（NSCLC）的一线化疗药物，但它经常导致获得性耐药，从而导致治疗失败。因此，筛选并表征能够使耐药癌细胞对化疗药物重新敏感的紫杉醇耐药逆转剂的机制至关重要。
采用细胞活力、成球和异种移植实验来评估ASIV逆转紫杉醇耐药的能力。应用免疫组织化学、细胞因子应用、小分子干扰RNA、小分子抑制剂和RNA测序方法来表征ASIV抑制表皮调节素（EREG）及其下游信号以逆转紫杉醇耐药的分子机制。
ASIV通过抑制NSCLC中球体的干性相关基因来逆转紫杉醇耐药。机制探索表明，ASIV促进EREG的K48连接的多聚泛素化并导致其降解。此外，化疗药物处理可触发EREG。因此，EREG与ErbB受体结合并激活ERK信号，以调节干性相关基因的表达。抑制EREG/ErbB/ERK可通过抑制干性相关基因来逆转紫杉醇耐药。最后，观察到TGFβ和Hedgehog信号在EREG/ErbB/ERK的下游，可使用抑制剂靶向这些信号以逆转NSCLC的紫杉醇耐药。
这些发现表明，ASIV通过EREG/ErbB/ERK-TGFβ、Hedgehog轴抑制NSCLC的干性来逆转紫杉醇耐药。
