异位表达
癌症研究
细胞生物学
细胞凋亡
癌细胞
基因敲除
紫杉醇
生物
化学
癌症
细胞培养
生物化学
遗传学
作者
Xiaochao Wang,Yan Hao,Jianfeng Chen,Peipei Ding,Xinyue Lv,Danlei Zhou,Ling Li,Luying Li,Yanqing Xu,Yu-Meng Zhu,Wei Zhang,Lu Chen,Tian Liao,Xianghuo He,Qinghai Ji,Weiguo Hu
出处
期刊:Research Square - Research Square
日期:2023-01-30
标识
DOI:10.21203/rs.3.rs-2456148/v1
摘要
Abstract In addition to the classical role as a serum effector system of innate immunity, accumulating evidence suggests that intracellular complement components have indispensable functions in immune defense, T cell homeostasis, and tumor cell proliferation and metastasis. Here, we revealed that complement component 3 (C3) is remarkably upregulated in paclitaxel (PTX)-resistant non-small cell lung cancer (NSCLC) cells and that knockdown of C3 promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy. Ectopic C3 decreased PTX-induced apoptosis and induced resistance to PTX treatment in original NSCLC cells. Interestingly, C3b, the activated fragment of C3, was found to translocate into the nucleus and physically associate with the HDAC1/2-containing SIN3A complex to repress the expression of GADD45A, which plays an important role in cell growth inhibition and apoptosis induction. Importantly, C3 downregulated GADD45A by enhancing the binding of the SIN3A complex with the promoter of GADD45A, thus decreasing the H3Ac level to compress chromatin around the GADD45A locus. Subsequently, ectopic GADD45A promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy, and insufficiency of GADD45A in original cancer cells induced resistance to PTX treatment. These findings identify a previously unknown nucleus location and oncogenic property for C3 in chemotherapy and provide a potential therapeutic opportunity to overcome PTX resistance.
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