In 2000, the National Cancer Institute Anticancer Drug Screen found that the strongest correlation between cancer-related gene expression and resistance to chemotherapeutic agents was for BCL-XL. In the 4 October issue of Cell, Benjamin Deverman and colleagues provide evidence that BCL-XL has a functional role in resisting apoptosis that is caused by cisplatin and other anticancer agents.
DNA-damaging anticancer therapeutics are effective because they induce apoptosis in tumour cells. As the BCL2 family has a central role in apoptosis, Deverman et al. focused on these proteins, and, in particular, on BCL-XL, which inhibits apoptosis by blocking activity of the proapoptotic branch of the BCL2 family — the BH3-only proteins. They decided to use TP53 -null, RB -null osteosarcoma cells (SAOS-2), which are susceptible to cisplatin-induced apoptosis, to study the apoptosis pathways, because both TP53 and RB are either mutated or functionally inactivated in most tumours.
So, what effect did treatment of SAOS-2 cells with cisplatin have on BCL2 and BCL-XL? Whereas BCL2 was unaffected in treated cells, BCL-XL was found to be modified by deamidation — asparagines are converted to a mixture of aspartates and isoaspartates — at two conserved sites, asparagines 52 and 66. This deamidation correlated with the timing of cell death. Unlike the wild-type BCL-XL protein, the constitutively deamidated BCL-XL could not bind to BH3-only proteins and this might contribute to the inability of BCL-XL to block cisplatin-induced apoptosis in SAOS-2 cells.
If RB expression was induced in SAOS-2 cells, BCL-XL deamidation was suppressed, which allowed cells to resist DNA-damage-induced apoptosis. In addition, the use of BCL-XL antisense rendered RB-expressing SAOS-2 cells sensitive to cisplatin. Deverman et al. concluded that SAOS-2 fibroblasts are dependent on BCL-XL activity for their resistance to cisplatin.
The authors are now concentrating on determining the mechanism by which deamidation is regulated. A better understanding of how the BCL2 family respond to DNA-damaging agents, and their role in drug resistance, should help the development of new therapeutic approaches.
References
ORIGINAL RESEARCH PAPER
Deverman, B. J. et al. Bcl-XL deamidation is a critical switch in the regulation of the response to DNA damage. Cell 111, 51–62 (2000)
FURTHER READING
Amundson, S. A. et al. An informatics approach identifying markers of chemosensitivity in human cancer cell lines. Cancer Res. 60, 6101–6110 (2000)
Cory, S. & Adams, J. M. The BCL2 family: regulators of the cellular life-or-death switch. Nature Rev. Cancer 2, 647–656 (2002)
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Hutchinson, E. Damage limitation. Nat Rev Cancer 2, 808 (2002). https://doi.org/10.1038/nrc931
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DOI: https://doi.org/10.1038/nrc931