Article

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

Sanford/Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Cell Death & Disease (Impact Factor: 5.18). 05/2010; 1(5):e40. DOI: 10.1038/cddis.2010.18
Source: PubMed

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.

Download full-text

Full-text

Available from: William Placzek, Feb 10, 2014
1 Follower
 · 
125 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Investigations from multiple laboratories support the existence of melanoma initiating cells (MICs) that potentially contribute to melanoma's drug resistance. ABT-737, a small molecule BCL-2/BCL-XL/BCL-W inhibitor, is promising in cancer treatments, but not very effective against melanoma, with the anti-apoptotic protein MCL-1 as the main contributor to resistance. The synthetic retinoid fenretinide (4-HPR) has shown promise for treating breast cancers. Here, we tested whether the combination of ABT-737 with 4-HPR is effective in killing both the bulk of melanoma cells and MICs. The combination synergistically decreased cell viability and caused cell death in multiple melanoma cells lines (carrying either BRAF or NRAS mutations), but not in normal melanocytes. The combination increased the NOXA expression and caspase-dependent MCL-1 degradation. Knocking-down NOXA protected cells from combination-induced apoptosis, implicating the role of NOXA in the drug synergy. The combination treatment also disrupted primary spheres (a functional assay for MICs) and decreased the percentage of ALDH(high) cells (a marker of MICs) in melanoma cell lines. Moreover, the combination inhibited the self-renewal capacity of MICs, measured by secondary sphere forming assays. In vivo, the combination inhibited tumor growth. Thus, this combination is a promising treatment strategy for melanoma, regardless of mutation status of BRAF or NRAS.Journal of Investigative Dermatology accepted article preview online, 28 October 2014. doi:10.1038/jid.2014.464.
    Journal of Investigative Dermatology 10/2014; 135(3). DOI:10.1038/jid.2014.464 · 6.37 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Mitochondrial outer membrane permeabilization (MOMP) is one of the most important points in the majority of apoptotic signaling cascades and it is controlled by a network of interactions between the members of the Bcl-2 family. Methods To understand the role of individual members of this family within the MOMP regulation, we have constructed a Boolean network-based model of interactions between the Bcl-2 proteins. Results Computational simulations have revealed the existence of trapping states which, independently from the incoming stimuli, block the occurrence of MOMP. Our results emphasize the role of the antiapoptotic protein Mcl-1 in the majority of these configurations. We demonstrate here the importance of the Bid and Bim for activation of effectors Bax and Bak, and the irreversibility of this activation. The model further points to the antiapoptotic protein Bcl-w as a key factor preventing Bax activation. Conclusions In spite of relative simplicity, the Boolean network-based model provides useful insight into main functioning logic of the Bcl-2 switch, consistent with experimental findings.
    Theoretical Biology and Medical Modelling 06/2013; 10(1):40. DOI:10.1186/1742-4682-10-40 · 1.27 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: While numerous cell signaling pathways are known to play decisive roles in chemotherapeutic response, relatively little is known about the impact of the Smad-dependent transforming growth factor β pathway on the therapeutic outcome. Previous reports suggested that patients with lung cancer who continue to smoke while receiving chemotherapy have a poorer outcome than their nonsmoking counterparts do. In our previous study, we showed that long-term cigarette smoke condensate (CSC)-mediated down-regulation of Smad3 induces tumorigenesis. The objective of this study was to determine the mechanism of function of Smad3 in chemoresistance induced by CSC in human lung cell lines, namely, A549 and HPL1A. Long-term CSC treatment increases the half-maximal inhibitory concentration (IC(50)) of carboplatin and makes cells resistant to carboplatin. The increase in IC(50) of long-term CSC-treated cells is due to the reduced induction in apoptosis by carboplatin. The increase in IC(50) and decrease in apoptosis in long-term CSC-treated cells is correlated with the expression of Bcl2. We have determined that Bcl2 is both necessary and sufficient to make the cells resistant to carboplatin. We have also shown that Smad3 acts upstream to regulate the expression of Bcl2 specifically and, thus, sensitivity of the cells to carboplatin. This is supported by the inverse correlation between the expressions of Smad3 and Bcl2 in human lung tumors. Collectively, these data suggest that loss of Smad3 expression in CSC-treated cells induces resistance to carboplatin by upregulating the expression of Bcl2. This study explains, at least in part, the higher chemoresistance rate observed in smokers.
    Neoplasia (New York, N.Y.) 07/2012; 14(7):644-55. DOI:10.1593/neo.12548 · 5.40 Impact Factor