Article

Placzek WJ, Wei J, Kitada S et al.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. Cell Death Dis 1:e40

Sanford/Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Cell Death & Disease (Impact Factor: 5.01). 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.

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    • "Placzek and co-workers investigated the mRNA expression levels of all six antiapoptotic Bcl-2 subfamily members in 68 human cancer cell lines [7]. The study revealed that Mcl-1 represents the antiapoptotic Bcl-2 subsfamily member with the highest mRNA level in the lung, prostate, breast, ovarian, renal, and glima cell lines [7]. "
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    ABSTRACT: A phytochemical study of the EtOAc-soluble part of the methanolic extract of the bark of Endiandra kingiana led to the isolation of three new pentacyclic kingianins as racemic mixtures, kingianins O–Q (1–3), together with the known kingianins A, F, K, L, M and N (4–9), respectively. The structures of the new kingianins 1–3 were determined by 1D and 2D NMR analysis in combination with HRESIMS experiments. Kingianins A–Q were assayed for Mcl-1 binding affinity. Kingianins G and H were found to be potent inhibitors of Mcl-1/Bid interaction. A structure–activity relationship study showed that potency is very sensitive to the substitution pattern on the pentacyclic core. In addition, in contrast with the binding affinity for Bcl-xL, the levorotatory enantiomers of kingianins G, H and J exhibited similar binding affinities for Mcl-1 than their dextrorotatory counterparts, indicating that the two anti-apoptotic proteins have slightly different binding profiles.
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    • "Although it occurs with low efficiency, Mcl-1 may undergo an additional AS event to produce an extrashort Mcl-1 form (Mcl-1ES) that interacts with Mcl-1L and induces the mitochondrial cell death pathway (Kim et al., 2009). Given the clear association between defective apoptosis and cancer and because Mcl-1 is often overexpressed in several types of human tumors (Derenne et al., 2002; Khoury et al., 2003; Placzek et al., 2010; Perciavalle and Opferman, 2013), many attempts have been made to reestablish cellular sensitivity to apoptosis by modulating Mcl-1 expression. Developments in the study of apoptosis have also uncovered a central role for mitochondrial morphology. "
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    ABSTRACT: The Bcl-2 (B-cell lymphoma-2) family proteins are critical regulators of apoptosis and consist of both pro- and anti-apoptotic factors. Within this family, the myeloid cell leukemia factor 1 (Mcl-1) protein exists in two forms as the result of alternative splicing. The long variant (Mcl-1L) acts as an anti-apoptotic factor, whereas the short isoform (Mcl-1S) displays pro-apoptotic activity. In this study, using splice-switching antisense oligonucleotides (ASOs), we increased the synthesis of Mcl-1S, which induced a concurrent reduction of Mcl-1L, thus resulting in the increased sensitivity of cancer cells to apoptotic stimuli. The Mcl-1 ASOs also induced mitochondrial hyperpolarization and a consequent increase in mitochondrial calcium (Ca2+) accumulation. The high Mcl-1S/L ratio was correlated with significant hyperfusion of the entire mitochondrial network, which occurred in a Dynamin-related protein (Drp1)-dependent manner. Our data indicate that the balance between the long and short variants of the Mcl-1 gene represents a key aspect of the regulation of mitochondrial physiology. Moreover, we propose that the Mcl-1L/S balance is a novel regulatory factor controlling the mitochondrial fusion and fission machinery.
    No preview · Article · Oct 2015 · Molecular biology of the cell
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    • "Besides to mainly localize in the mitochondrial membrane, Mcl-1 has also been found in the nucleus and the cytoplasm [7]. Mcl-1 is highly expressed in a variety of human tumor tissues, such as breast cancer, colon cancer, lung cancer, ovarian cancer, prostate cancer, kidney cancer, and liver cancer [8] [9]. Although overexpression of Mcl-1 does not directly promote the proliferation of tumor cells, its ability to suppress apoptosis plays a key role for cancer cell to protect against the apoptosis-inducing effect caused by toxic factors. "
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