Non-apoptotic Roles of Caspases in Stem Cell Biology, Carcinogenesis, and Radiotherapy
- 2 Downloads
Purpose of Review
To summarize recent findings on novel roles of caspases in stem cell biology, tumor repopulation, and tissue regeneration. Contrary to the long-held notion that apoptotic caspases are exclusively executioners of programmed cell death, an abundance of evidence is emerging that activation of caspases does not inevitably lead to cell death.
It is now known that sublethal activation of caspases occurs in development, stem cell differentiation, epigenetic reprogramming, and a whole host of other key biological processes. Important for cancer biology, recent studies show that activation of caspases in tumors facilitates carcinogenesis, metastasis, and tumor relapse after cancer treatment. We have found that apoptotic cells secrete prostaglandins to stimulate proliferation of neighboring cells. This pathway functions to regenerate tissues and stem cells in multiple organisms, but it also poses problems in emerging tumor resistance to chemotherapy and radiotherapy.
Novel findings on caspases are contrary to established paradigms and might explain why cancer therapies aimed at activating apoptotic caspases have not been very successful in the clinic. In this brief review, we summarize some novel findings regarding caspases with the hope of stimulating more interest in this nascent but increasingly important research area. Better understanding of the diverse roles of caspases may one day help us establish novel approaches for treating cancer.
KeywordsStem cell Ionizing radiation Apoptotic caspases Cancer stem cell Carcinogenesis Epigenetic reprogramming
Work in our laboratory is supported by grants CA208852, CA216876, and ES024015 from the US National Institutes of Health.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
Data described in this study is approved by the Duke University Institutional Animal Care and Use Committee.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 14.Baena-Lopez, L.A., et al., Non-apoptotic caspase regulation of stem cell properties. Semin Cell Dev Biol. 2018;82:118-126.Google Scholar
- 39.• Cartwright, I.M., et al., Essential roles of caspase-3 in facilitating Myc-induced genetic instability and carcinogenesis. Elife, 2017;6:e26371. https://doi.org/10.7554/eLife.26371. This report provides strong evience for the importance of Casp3-mediatd double strand breaks in Myc induced carcinogenesis.
- 40.• Ding, A.X., et al., CasExpress reveals widespread and diverse patterns of cell survival of caspase-3 activation during development in vivo. Elife, 2016;5:e10936. https://doi.org/10.7554/eLife.10936. This report elegantly demonstrate cellular surival after Casp3 activation in vivo and implicating its imporatnt roles in cellular differentiation.
- 46.• Liu X, et al. Self-inflicted DNA double-strand breaks sustain tumorigenicity and stemness of cancer cells. Cell Res. 2017;27(6):764–83. This report provides evidence for low level leakage of mitochondria, which leads to caspase activation and DNA doule strand breaks, and enhanced tumorigenicity in cancer cells. Google Scholar
- 52.•• Huang Q, et al. Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat Med. 2011;17(7):860–6. This report provides strong evidence for a paradoxical role for Casp3 in promoting PGE 2 production and tumor repopulation after radiotherapy. Google Scholar
- 54.• Kurtova AV, et al. Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance. Nature. 2015;517(7533):209–13. This report suggests that chemotherapy of bladder induced apoptosis promotes PGE2 secretion from dying cells, which stimulates cancer stem cell activation and tumor resistance to therapy. PubMedCrossRefGoogle Scholar
- 72.Rideout HJ, Stefanis L. Caspase inhibition: a potential therapeutic strategy in neurological diseases. Histol Histopathol. 2001;16(3):895–908.Google Scholar
- 73.Sanchez Mejia RO, Friedlander RM. Caspases in Huntington's disease. Neuroscientist. 2001;7(6):480–9.Google Scholar