Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
Cell Death Dis. 2024 Jun 15;15(6):417. doi: 10.1038/s41419-024-06817-0.
Chemotherapy is a crucial treatment for colorectal tumors. However, its efficacy is restricted by chemoresistance. Recently, Golgi dispersal has been suggested to be a potential response to chemotherapy, particularly to drugs that induce DNA damage. However, the underlying mechanisms by which Golgi dispersal enhances the capacity to resist DNA-damaging agents remain unclear. Here, we demonstrated that DNA-damaging agents triggered Golgi dispersal in colorectal cancer (CRC), and cancer stem cells (CSCs) possessed a greater degree of Golgi dispersal compared with differentiated cancer cells (non-CSCs). We further revealed that Golgi dispersal conferred resistance against the lethal effects of DNA-damaging agents. Momentously, Golgi dispersal activated the Golgi stress response via the PKCα/GSK3α/TFE3 axis, resulting in enhanced protein and vesicle trafficking, which facilitated drug efflux through ABCG2. Identification of Golgi dispersal indicated an unexpected pathway regulating chemoresistance in CRC.
化疗是结直肠肿瘤的重要治疗方法。然而，其疗效受到化疗耐药性的限制。最近，高尔基分散被认为是对化疗的一种潜在反应，特别是对诱导 DNA 损伤的药物。然而，高尔基分散增强抵抗 DNA 损伤药物能力的潜在机制尚不清楚。在这里，我们证明 DNA 损伤药物在结直肠癌 (CRC) 中引发高尔基分散，并且癌症干细胞 (CSC) 比分化癌细胞 (非 CSC) 具有更大程度的高尔基分散。我们进一步揭示了高尔基分散赋予了对 DNA 损伤药物致命作用的抗性。重要的是，高尔基分散通过 PKCα/GSK3α/TFE3 轴激活了高尔基体应激反应，导致蛋白质和囊泡转运增强，从而通过 ABCG2 促进药物外排。高尔基分散的鉴定表明了一种调节 CRC 化疗耐药性的意外途径。
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