A survey of the anti-apoptotic Bcl-2 subfamily expression in cancer types provides a platform to predict the efficacy of Bcl-2 antagonists in cancer therapy

Abstract

We investigated the mRNA expression levels of all six antiapoptotic Bcl-2 subfamily members in 68 human cancer cell lines using qPCR techniques and measured the ability of known Bcl-2 inhibitors to induce cell death in 36 of the studied tumor cell lines. Our study reveals that Mcl-1 represents the anti-apoptotic Bcl-2 subfamily member with the highest mRNA levels in the lung, prostate, breast, ovarian, renal, and glioma cancer cell lines. In leukemia/lymphoma and melanoma cancer cell lines, Bcl-2 and Bfl-1 had the highest levels of mRNA, respectively. The observed correlation between the cell killing properties of known Bcl-2 inhibitors and the relative mRNA expression levels of anti-apoptotic Bcl-2 proteins provide critical insights into apoptosis-based anticancer strategies that target Bcl-2 proteins. Our data may explain current challenges of selective Bcl-2 inhibitors in the clinic, given that severe expression of Bcl-2 seems to be limited to leukemia cell lines. Furthermore, our data suggest that in most cancer types a strategy targeted to Mcl-1 inhibition, or combination of Bfl-1 and Mcl-1 inhibition for melanoma, may prove to be more successful than therapies targeting only Bcl-2.

miR-200 promotes the mesenchymal to epithelial transition by suppressing multiple members of the Zeb2 and Snail1 transcriptional repressor complexes

“…Moreover, MCL-1 expression is linked to poor prognosis in TNBC (Ding et al, 2007;Placzek et al, 2010). However, although NOXA is also highly upregulated by proteasome inhibition in mesenchymal TNBC lines, they are resistant to bortezomib and are not dependent on MCL-1.…”

Cdk2 acts upstream of mitochondrial permeability transition during paclitaxel-induced apoptosis

“…Firstly, Bcl-2 family proteins act as gatekeepers in controlling the release of cytochrome c from mitochondria (Breckenridge and Xue, 2004;Willis and Adams, 2005;Chipuk and Green, 2008). Pro-apoptotic Bcl-2 proteins induce the mitochondrial cytochrome c release whereas overexpressed anti-apoptotic Bcl-2 proteins prevent it (Placzek et al, 2010). Secondly, the process of apoptosome formation and caspase-9 autoactivation can be negatively regulated by Hsp-70 and Hsp-90, which prevents the oligomerization of Apaf-1 and its association with procaspase-9 (Beere et al, 2000;Pandey et al, 2000;Saleh et al, 2000;Garrido et al, 2006).…”

Structure-Function Analysis of the Mcl-1 Protein Identifies a Novel Senescence-regulating Domain

“…We have determined previously that Mcl-1 also possesses a unique ability to abrogate chemotherapy-induced senescence (CIS) 2 both in vitro and in vivo (11). Surprisingly, untreated Mcl-1-depleted tumors xenografted into nude mice had significant impairment of tumor growth, not by an apoptotic mechanism but, instead, by undergoing a spontaneous form of senescence.…”

“…Among the molecules mediating these prosurvival effects are members of the Bcl-2 family, proteins now known to be key drivers of oncogenesis and growth in most human cancers. Large studies assessing somatic copy numbers of oncogenic proteins reveal that two members of the Bcl-2 family, Bcl-2 and Mcl-1, are particularly elevated in many forms of human cancer (1,2). Characterizing these prosurvival proteins is a common canonical binding groove that sequesters and neutralizes proapoptotic proteins (3) and, therefore, is presumed to be essential for mediating tumor development and progression and resistance to therapeutic intervention (4) Consequently, continuous efforts are focused on developing inhibitors of this binding groove, with several candidate inhibitors already in clinical trials (5).…”