Targeting p53 to mitochondria for cancer therapy

Although the tumor suppressor protein p53 is a major senescence- and cell death-inducing transcription factor, recent work has clearly demonstrated that p53 has additional, extranuclear effects that contribute to its cell cycle-arresting and proapoptotic functions. Mitochondrial outer membrane permeabilization (MOMP) is (one of) the most prominent apoptotic checkpoint(s), and cytoplasmic p53 can induce MOMP by direct interactions with multidomain proteins from the Bcl-2 family present at the mitochondrial outer membrane (OM). Since MOMP is commonly disabled in cancer cells, its pharmacological induction constitutes a therapeutic goal, and this has stimulated the design of mitochondriotropic inducers of apoptosis, both inhibitors of antiapoptotic Bcl-2 family proteins (e.g., Bcl-2, Bcl-X_L) or activators of their proapoptotic counterparts (e.g., Bak, Bax). Moreover, novel approaches of gene therapy have been designed in which p53 is specifically targeted to mitochondria and have been demonstrated to inhibit the growth of human cancer xenografts in immunodeficient mice. Thus, a number of distinct strategies can be employed to achieve the therapeutic induction of MOMP in cancer cells.