Antiapoptotic Bcl-2 family members, including Bcl-xL, are often overexpressed in a variety of cancers through genetic alterations. Bcl-xL is wellknown for its antiapoptotic function, which is critical to the development and survival of multicellular organisms. The function of Bcl-xL in tumorigenesis has been ascribed to its antiapoptotic activity. In addition to its antiapoptotic function, other functions of Bcl-xL have been discovered, such as that Bcl-xL promotes migration, invasion, and metastasis. Mutations in proteins play an important role in the onset and development of cancer. Mutations may affect protein folding and stability, protein function, and protein-protein interactions, as well as protein expression and subcellular localization. Large-scale cancer genome projects have reported lists of mutations in various tumor types and this information has facilitated subsequent investigations into the functions of these mutant proteins, as well as further therapeutic development of mutation-specific therapeutics to target the mutant proteins. Cancer patient-associated mutations of Bcl-xL have been identified with unknown functional impact. In this study, the authors investigate whether these cancer patientassociated mutations of Bcl-xL affect its functions in antiapoptosis, cell migration, and nuclear translocation. 

Here, the authors selected four patient-associated Bcl-xL mutations, R132W, N136K, R165W, and A201T (Fig. 1), to investigate their impacts on antiapoptosis, migration, and nuclear translocation. They found that all four mutation proteins could be detected in both the nucleus and cytosol. Although all four mutations disrupted the antiapoptosis function, one of these mutants, N136K, significantly improved the ability to promote cell migration. These data suggest the importance of developing novel Bcl-xL inhibitors to ablate both antiapoptotic and prometastatic functions of Bcl-xL in cancer.

Fig.1 The selected patient-associated mutations are at critical positions of Bcl-xL

Article Access: https://onlinelibrary.wiley.com/doi/full/10.1002/mco2.36