Key Points
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Resistance to apoptosis is considered to be a hallmark of cancer cells. Defects in apoptosis underlie not only tumorigenesis, but also resistance to cancer treatments.
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Defects in non-apoptotic cell-death pathways — such as necrosis, autophagy and mitotic catastrophe — are also associated with tumorigenesis. The senescence 'living-death' programme — which involves the genes that encode p53, WAF1, INK4A and the retinoblastoma protein — is crucial for both tumour suppression and anticancer therapy.
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Malignant transformation can be induced by the dysregulation of oncogenes and tumour-suppressor genes that have secondary functions in the autophagic pathway. Inactivation of the autophagy gene beclin 1 induces malignancy in a mouse model.
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Defects in genes that are required for mitotic catastrophe can contribute to tumorigenesis. Uncontrolled activation of mitotic kinases and defects in mitotic checkpoints are important causes of centrosomal aberrations and genomic instability.
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Survivin is essential for mitotic progression, and inactivation of this protein induces death by mitotic catastrophe. Survivin might be an ideal target for cancer treatment, because cell death induced by survivin loss is independent of BCL2 and p53.
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The interactions between non-apoptotic and apoptotic cell-death pathways are not yet clear. Further investigation of non-apoptotic pathways might reveal new targets for the design of therapeutics that are aimed at inducing the non-apoptotic death of cancer cells.
Abstract
Defects in cell-death pathways are hallmarks of cancer. Although resistance to apoptosis is closely linked to tumorigenesis, tumour cells can still be induced to die by non-apoptotic mechanisms, such as necrosis, senescence, autophagy and mitotic catastrophe. The molecular pathways that underlie these non-apoptotic responses remain unclear. Several apoptotic and non-apoptotic pathways of cell death have been defined in normal physiology and during tumorigenesis, and these could potentially be manipulated to develop new cancer therapies. The mitotic-checkpoint molecule survivin — the inactivation of which induces the death of p53-deficient cells by mitotic catastrophe — is of particular interest.
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Acknowledgements
We thank numerous current and former members of the Mak laboratory, and all colleagues and collaborators, for comments and helpful discussions. We also thank L. Harrington for critical reading of the manuscript and M. Saunders for scientific editing. We sincerely apologize that we are unable to refer to and fully acknowledge the many important contributions to this field.
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Glossary
- CRE–LOXP RECOMBINATION
-
A site-specific recombination system derived from bacteriophage P1. By flanking a gene of interest with loxP sites and expressing CRE recombinase under the control of an appropriate promoter, genomic manipulations such as deletion, integration, inversion or translocation of a gene of interest can be carried out in a tissue- or stage-specific manner.
- ENDODUPLICATION
-
A modified cell cycle in which S phase (DNA synthesis) occurs without M phase (mitosis and cell division). Large, polyploid cells result.
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Okada, H., Mak, T. Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer 4, 592–603 (2004). https://doi.org/10.1038/nrc1412
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DOI: https://doi.org/10.1038/nrc1412
