Mcl‐1 targeting could be an intriguing perspective to cure cancer

• Published in: Journal of cellular physiology Vol. 233; no. 11; pp. 8482 - 8498
• Main Authors: De Blasio, Anna, Vento, Renza, Di Fiore, Riccardo
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.11.2018
• Subjects: Apoptosis; Bcl‐2 family; Cancer; cancer care; cancer‐stem‐cells; Cell self-renewal; Chemotherapy; Clinical trials; Mcl‐1 in cancers; Mcl‐1 isoforms; Medical research; Phagocytosis; Post-transcription; Proteasomes; Proteins; Regulators; Senescence; Splicing; Stem cells; targeting Mcl‐1; Tumorigenesis; cancer care; Mcl-1 in cancers; Mcl-1 isoforms; targeting Mcl-1; cancer-stem-cells; Bcl-2 family
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.26786

The Bcl‐2 family, which plays important roles in controlling cancer development, is divided into antiapoptotic and proapoptotic members. The change in the balance between these members governs the life and death of the cells. Mcl‐1 is an antiapoptotic member of this family and its distribution in normal and cancerous tissues strongly differs from that of Bcl‐2. In human cancers, where upregulation of antiapoptotic proteins is common, Mcl‐1 expression is regulated independent of Bcl‐2 and its inhibition promotes senescence, a major barrier to tumorigenesis. Cancer chemotherapy determines various kinds of responses, such as senescence and autophagy; however, the ideal response to chemotherapy is apoptosis. Mcl‐1 is a potent oncogene that is regulated at the transcriptional, posttranscriptional, and posttranslational levels. Mcl‐1 is a short‐lived protein that, in the NH2 terminal region, contains sites for posttranslational regulation that can lead to proteasomal degradation. The USP9X Mcl‐1 deubiquitinase regulates Mcl‐1 and the levels of these two proteins are strongly correlated. Mcl‐1 has three splicing variants (the antiapoptotic protein Mcl‐1L and the proapoptotic proteins Mcl‐1S and Mcl‐1ES), each contributing toward apoptosis regulation. In cancers responsible for the most deaths in the world, the presence of Mcl‐1 is associated with malignant cell growth and evasion of apoptosis. Mcl‐1 is also one of the key regulators of cancer stem cells’ self‐renewal that contributes to tumor survival. A great number of indirect and selective Mcl‐1 inhibitors have been produced and some of these have shown efficacy in several clinical trials. Thus, therapeutic manipulation of Mcl‐1 can be a useful strategy to combat cancer. Mcl‐1 is an antiapoptotic member of the Bcl‐2 family; its upregulation is common in human cancers and its inhibition contributes toward promoting apoptosis, senescence, and autophagy. Mcl‐1 is regulated at the transcriptional, post‐transcriptional, and post‐translational levels, and its NH2 terminal region contains sites for posttranslational regulation that can lead to proteasomal degradation. Moreover, Mcl‐1 has three splicing variants, each contributing to apoptosis regulation. Mcl‐1 is a key regulator of cancer stem cells self‐renewal; thus, its therapeutic manipulation can be a useful strategy to combat cancer.