Mcl-1 is a Gate Keeper Regulating Cell Death in Cancer Cells

Abstract

Selectively inducing cancer cells to death is the goal of cancer therapy. The discovery of B-cell lymphoma 2 (Bcl-2) family members regulating apoptotic cell death of cancer cells revealed new targets for cancer therapy. Bcl-2 family members can be classified into pro-apoptotic members and anti-apoptotic members among which myeloid cell leukemia 1 (Mcl-1) plays unique roles in regulating cell death and survival in cancer cells. Mcl-1 has a short half-life due to its degradation by multiple E3 ubiquitin-ligases. Under hypoxic conditions, Mcl-1 is up-regulated by activation of growth factor receptor, EGFR promoting cell survival whereas, prolonged/severe hypoxia leads to deactivation of EGFR and Mcl-1 degradation by E3 ubiquitin -ligase FBW7 contributing to cell death. Furthermore, cancer cells upregulated Mcl-1 contributing resistance to chemotherapeutic treatment such as by inhibitors of other antiapoptotic Bcl-2 members Bcl-2, Bcl-xL and Bcl-w. Therefore, Mcl- 1 might be the key player in pro-survival Bcl-2 family members in regulating cancer cell death. This encourages the on-going active development of Mcl-1 specific inhibitors for cancer treatment.