Mcl-1 antagonism is a potential therapeutic strategy in a subset of solid cancers

作者：Modugno Michele^*; Banfi Patrizia; Gasparri Fabio; Borzilleri Robert; Carter Percy; Cornelius Lyndon; Gottardis Marco; Lee Ving; Mapelli Claudio; Naglich Joseph G; Tebben Andrew; Vite Gregory; Pastori Wilma; Albanese Clara; Corti Emiliana; Ballinari Dario; Galvani Arturo

来源：Experimental Cell Research, 2015, 332(2): 267-277.

DOI：10.1016/j.yexcr.2014.11.022

• Mcl-1
• SiRNA
• Apoptosis
• Cancer
• Mitochondria

Cancer cell survival is frequently dependent on the elevated levels of members of the BcI-2 family of prosurvival proteins that bind to and inactivate BH3-domain pro-apoptotic cellular proteins. Small molecules that inhibit the protein protein interactions between prosurvival and proapoptotic BcI-2 family members (so-called "BH3 mimetics") have a potential therapeutic value, as indicated by clinical findings obtained with ABT-263 (navitoclax), a BcI-2/BcI-xL antagonist, and more recently with GDC-0199/ABT-199, a more selective antagonist of BcI-2. Here, we report study results of the functional role of the prosurvival protein Mcl-1 against a panel of solid cancer cell lines representative of different tumor types. We observed silencing of Mcl-1 expression by small interfering RNAs (siRNAs) significantly reduced viability and induced apoptosis in almost 30% of cell lines tested, including lung and breast adenocarcinoma, as well as glioblastoma derived lines. Most importantly, we provide a mechanistic basis for this sensitivity by showing antagonism of Mcl-1 function with specific BH3 peptides against isolated mitochondria induces Bak oligomerization and cytochrome c release, therefore demonstrating that mitochondria from Mcl-l-sensitive cells depend on Mcl-1 for their integrity and that antagonizing Mcl-1 function is sufficient to induce apoptosis. Thus, our results lend further support for considering Mcl-1 as a therapeutic target in a number of solid cancers and support the rationale for development of small molecule BH3-mimetics antagonists of this protein.

• 出版日期2015-3-15