IFOM ETS - The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milano, Italy.
IFOM ETS - The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milano, Italy.
Cell Rep. 2023 Mar 28;42(3):112215. doi: 10.1016/j.celrep.2023.112215. Epub 2023 Mar 13.
Drugs targeting microtubules rely on the mitotic checkpoint to arrest cell proliferation. The prolonged mitotic arrest induced by such drugs is followed by a G1 arrest. Here, we follow for several weeks the fate of G1-arrested human cells after treatment with nocodazole. We find that a small fraction of cells escapes from the arrest and resumes proliferation. These escaping cells experience reduced DNA damage and p21 activation. Cells surviving treatment are enriched for anti-apoptotic proteins, including Triap1. Increasing Triap1 levels allows cells to survive the first treatment with reduced DNA damage and lower levels of p21; accordingly, decreasing Triap1 re-sensitizes cells to nocodazole. We show that Triap1 upregulation leads to the retention of cytochrome c in the mitochondria, opposing the partial activation of caspases caused by nocodazole. In summary, our results point to a potential role of Triap1 upregulation in the emergence of resistance to drugs that induce prolonged mitotic arrest.
靶向微管的药物依赖有丝分裂检查点来阻止细胞增殖。此类药物引起的有丝分裂阻滞延长后，会出现 G1 期阻滞。在这里，我们在使用诺考达唑处理后，对 G1 期阻滞的人细胞的命运进行了数周的跟踪研究。我们发现一小部分细胞逃脱了阻滞并恢复了增殖。这些逃脱的细胞经历了较少的 DNA 损伤和 p21 激活。存活下来的细胞富含抗凋亡蛋白，包括 Triap1。增加 Triap1 的水平可以使细胞在第一次处理时减少 DNA 损伤和 p21 的水平，从而降低细胞对诺考达唑的敏感性；相应地，降低 Triap1 水平可以使细胞对诺考达唑重新敏感。我们表明，Triap1 的上调导致细胞色素 c 在线粒体中的保留，从而拮抗了诺考达唑引起的半胱天冬酶的部分激活。总之，我们的结果表明 Triap1 的上调可能在对诱导长时间有丝分裂阻滞的药物产生耐药性方面发挥作用。
