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Caspase 3–mediated stimulation of tumor cell repopulation during cancer radiotherapy

2011; Nature Portfolio; Volume: 17; Issue: 7 Linguagem: Inglês

10.1038/nm.2385

1546-170X

Qian Huang, Fang Li, Xinjian Liu, Wenrong Li, Wei Shi, Fei‐Fei Liu, Brian O’Sullivan, Zhimin He, Yuanlin Peng, Aik Choon Tan, Ling Zhou, Jingping Shen, Gangwen Han, Xiao‐Jing Wang, Jackie Thorburn, Andrew Thorburn, Antonio Jimeno, David Raben, Joel S. Bedford, Chuan‐Yuan Li,

Mitochondrial Function and Pathology

Cytotoxic cancer therapy can induce accelerated growth of surviving cancer cells, a phenomenon known as tumor repopulation. This report uncovers a mechanism by which caspase 3 activation in treated cells promotes growth of surviving cells, mediated by iPLA2 and PGE2. The level of caspase 3 activation in human tumors also correlates with risk of relapse, suggesting that this pathway may be a determinant of therapeutic effects. In cancer treatment, apoptosis is a well-recognized cell death mechanism through which cytotoxic agents kill tumor cells. Here we report that dying tumor cells use the apoptotic process to generate potent growth-stimulating signals to stimulate the repopulation of tumors undergoing radiotherapy. Furthermore, activated caspase 3, a key executioner in apoptosis, is involved in the growth stimulation. One downstream effector that caspase 3 regulates is prostaglandin E2 (PGE2), which can potently stimulate growth of surviving tumor cells. Deficiency of caspase 3 either in tumor cells or in tumor stroma caused substantial tumor sensitivity to radiotherapy in xenograft or mouse tumors. In human subjects with cancer, higher amounts of activated caspase 3 in tumor tissues are correlated with markedly increased rate of recurrence and death. We propose the existence of a cell death–induced tumor repopulation pathway in which caspase 3 has a major role.