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

Abstract

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.

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Figure 1: In vitro and in vivo evidence for the generation of strong growth-stimulating signals in dying cells.
Figure 2: The role of caspase 3 in cell death–induced tumor cell proliferation in vitro and in vivo.
Figure 3: Relationship between caspase activation and growth of injected tumor cells in the irradiated tumor microenvironment.
Figure 4: A role for caspase 3–activated iPLA2 (Pla2g6) in facilitating cell death–stimulated tumor cell repopulation.
Figure 5: Regulation of radiation-induced arachidonic acid release and PGE2 production by caspase 3.
Figure 6: Caspase 3 status correlated with tumor response to therapy in mice as well as in human subjects.

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Acknowledgements

We thank R. Flavell of Yale University for providing us with MEF cells with caspase 3 or 7 deficiencies. We thank B. Liu of University of Colorado School of Medicine for providing us with the MCF-7 and MCF-7CASP3 cells. We also thank P. Kabos for insightful discussions. This study was supported in part by grants CA131408 and CA136748 from the US National Cancer Institute (to C.-Y.L.), and grant NNX09AH19G (to C.-Y.L.) from US National Aeronautics and Space Administration Ground-based Space Radiation Biology Research Program. It was also supported by a subcontract (to C.-Y.L.) of grant DEFG0207ER64350 (to J.S.B.) from the US Department of Energy Low Dose Radiation Research Program. Q.H. was supported by grant 2010CB529900 from the National Basic Research Project of China and Outstanding Young Scientist grants 30325043 & 30428015 from China National Natural Science Foundation.

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Contributions

Q.H. and F.L. designed and conducted most of the experiments, analyzed data and wrote the manuscript. X.L. and W.L. carried out analyses on modes of cell death in irradiated cells; W.S. carried out immunohistochemical analysis of human head and neck tumor samples; F.-F.L. and B.O. provided human head and neck cancer samples and analyzed data from the samples; Z.H. conducted some of the caspase reporter experiments; Y.P. carried out arachidonic acid release experiments and J.S.B. analyzed relevant data of arachidonic acid release; A.-C.T. carried out data analyses of human clinical data; G.H. and X.-J.W. helped with immunohistochemical analysis of mouse tumor samples; J.S. constructed some of the plasmids used; A.J. and D.R. provided human head and neck tumor samples; L.Z. carried out immunohistochemical analysis of human breast cancer samples; J.T. and A.T. helped to conduct experiments on autophagy and necrosis; C.-Y.L. conceived of the study, analyzed data and wrote the manuscript. All authors read and agreed on the final manuscript.

Corresponding author

Correspondence to Chuan-Yuan Li.

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The authors declare no competing financial interests.

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Supplementary Figures 1–23, Supplementary Note, Supplementary Methods and Supplementary Tables 1–3 (PDF 2193 kb)

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Huang, Q., Li, F., Liu, X. et al. Caspase 3–mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat Med 17, 860–866 (2011). https://doi.org/10.1038/nm.2385

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