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.