Anastasis confers ovarian cancer cells increased malignancy through elevated p38 MAPK activation
Anastasis confers ovarian cancer cells increased malignancy through elevated p38 MAPK activation
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DOI：
10.1038/s41418-022-01081-1
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发表时间：
2022-11
影响因子：
12.4
通讯作者：
Lili Sun;C. Yao;Xiaojiao Li;Yuxing Wang;R. Wang;Molin Wang;Qiao Liu;D. Montell;C. Shao
中科院分区：
文献类型：
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作者：
Lili Sun;C. Yao;Xiaojiao Li;Yuxing Wang;R. Wang;Molin Wang;Qiao Liu;D. Montell;C. Shao
刽子手半胱氨酸天冬氨酸酶的激活曾被认为是细胞凋亡的不归路。然而，近年来，越来越多的证据表明，细胞可以通过一种称为ANASTASIS的过程，在被称为ANASTASIS的过程中，通过激活半胱氨酸天冬氨酸酶(Caspase)而存活下来。在这项研究中，我们开发了一个报告系统mCasExpress，以跟踪在半胱氨酸天冬氨酸酶激活后存活的哺乳动物细胞。我们证明，卵巢癌细胞在短暂暴露于凋亡刺激TRAIL或紫杉醇后，获得了增强的迁移。此外，转移性癌细胞分泌更多的促血管生成因子，使肿瘤血管生成、生长和转移。从机制上讲，我们证明了p38MAPK的激活是以caspase依赖的方式发生的，以响应促进转移的凋亡应激，即使在去除凋亡刺激后，p38MAPK在转移癌细胞中仍保持在较高的水平。重要的是，p38对于提高移植瘤细胞的迁移和血管生成能力是必不可少的。我们的工作揭示了转移是肿瘤血管生成和转移的潜在驱动因素。
Activation of executioner caspases was once considered as a point of no return in apoptosis. However, in recent years, accumulating evidence has demonstrated that cells can survive executioner caspase activation in response to apoptotic stimuli through a process called anastasis. In this study, we developed a reporter system, mCasExpress, to track mammalian cells that survive executioner caspase activation. We demonstrate that anastatic ovarian cancer cells acquire enhanced migration following their transient exposure to apoptotic stimulus TRAIL or Paclitaxel. Moreover, anastatic cancer cells secrete more pro-angiogenic factors that enable tumor angiogenesis, growth and metastasis. Mechanistically, we demonstrate that activation of p38 MAPK, which occurs in a caspase-dependent manner in response to apoptotic stress to promote anastasis, persists at a higher level in anastatic cancer cells even after removal of apoptotic stimuli. Importantly, p38 is essential for the elevated migratory and angiogenic capacity in the anastatic cells. Our work unveils anastasis as a potential driver of tumor angiogenesis and metastasis.