FAM98A promotes resistance to 5-fluorouracil in colorectal cancer by suppressing ferroptosis
FAM98A promotes resistance to 5-fluorouracil in colorectal cancer by suppressing ferroptosis
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DOI：
10.1016/j.abb.2022.109216
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发表时间：
2022-04-14
影响因子：
3.9
通讯作者：
Zhuang, Baoxiong
中科院分区：
文献类型：
--
作者：
He, Zhanke;Yang, Junbo;Zhuang, Baoxiong
背景：FAM 98 A是一种微管相关蛋白，参与细胞增殖和迁移，在上皮癌中经常失调。但它在结直肠癌（CRC）癌症发展中的作用仍然未知。方法：采用免疫组化方法检测FAM 98 A在大肠癌组织中的表达。我们还研究了异常表达对结直肠癌细胞体内外生物学行为的影响。免疫印迹和免疫沉淀用于筛选FAM 98 A相关的信号通路和下游因子。结果：FAM 98 A在结直肠癌组织和结直肠癌细胞系中表达上调。FAM 98 A过表达促进细胞增殖，5-FU回收抑制大肠癌细胞增殖，在体外和体内。此外，FAM 98 A的增强表达通过激活应激颗粒（SG）中xCT的翻译来抑制CRC细胞中的铁凋亡。此外，我们发现二甲双胍可以逆转CRC细胞中FAM 98 A介导的5-FU耐药性。结论：FAM 98 A基因在大肠癌的发生发展过程中起重要作用，为大肠癌的临床耐药研究提供了新的靶点。二甲双胍对5-FU治疗结直肠癌有增敏作用。
Background:FAM98A is a microtubule-associated protein involved in cell proliferation and migration, and is frequently dysregulated in epithelial cancers. But its role in the development of colorectal cancer (CRC) cancer remains unknown. Methods:Immunohistochemical analysis was performed to examine the expression of FAM98A in CRC samples. We also investigated the effects of abnormal expression on the biological behavior of colorectal cancer cells both in vitro and in vivo. Immunoblotting and immunoprecipitation were used to screen FAM98A-related signalling pathways and downstream factors. Results:FAM98A was upregulated in CRC tissues and CRC cell lines. Overexpression of FAM98A promoted cell proliferation and recovered 5-FU suppressed CRC cell proliferation both in vitro and in vivo. In addition, the Enhanced expression of FAM98A inhibited ferroptosis in CRC cells by activating the translation of xCT in stress granules (SGs). Furthermore, we identified that metformin could reverse FAM98A-mediated 5-FU resistance in CRC cells. Conclusions:Our results for the first time indicate that FAM98A plays a critical role in promoting CRC progression, which provides a novel target for clinical drug resistance of colorectal cancer. And metformin may sensitize 5-FU in the treatment of colorectal cancer.