Downregulation of Mcl-1 by daunorubicin pretreatment reverses resistance of breast cancer cells to TNF-related apoptosis-inducing ligand.
ABSTRACT The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent. However, tumor cells often develop resistance to TRAIL, limiting its therapeutic potential. To study the mechanism underlying TRAIL-resistance in breast cancer cells, we performed a high-throughput compound screen in MCF-7 cells. We identified daunorubicin as a potent sensitizer of TRAIL-induced apoptosis in MCF-7 cells. Daunorubicin in combination with subtoxic concentrations of recombinant human TRAIL induced massive apoptosis in MCF-7 cells. This combination was effective in TRAIL-resistant MDA-MB-231 and T47D breast cancer cells. By immunoblotting, we found that daunorubicin treatment induced loss of the anti-apoptotic protein, Mcl-1, in breast cancer cells. RNA interference experiments revealed that reduced expression of Mcl-1 sensitized MCF-7 cells to TRAIL. Together, these data suggest that Mcl-1 is a major contributor to TRAIL-resistance in breast cancer cells, and that reduction of Mcl-1 protein levels using DNA damaging agents is a promising approach for cancer therapy.
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ABSTRACT: Breast carcinogenesis is a multidimensional disease that has resisted drug-related solutions to date because of heterogeneity, disorganized spatiotemporal behavior of signal transduction cascades, cell cycle checkpoints, cell transition, plasticity, and impaired pro-apoptotic response. These synchronized oncogenic events, including protein-protein interaction, transcriptional-regulatory, and signaling networks, trigger genomic and transcriptional disturbances in TRAIL-mediated signaling network neighborhoods. Therefore, tumor cells often acquire the ability to escape death by suppressing cell death pathways that normally function to eliminate damaged and harmful cells. This review describes the TRAIL-mediated cell death signaling pathways, the interactions between these pathways, and the ways in which these pathways are deregulated in breast cancer.Journal of Membrane Biology 08/2012; · 2.48 Impact Factor
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ABSTRACT: The TNF-related apoptosis inducing ligand (TRAIL) has promising anti-cancer therapeutic activity, although significant percentage of primary tumors resistant to TRAIL-induced apoptosis remains an obstacle to the extensive use of TRAIL-based mono-therapies. Natural compound curcumin could potentially sensitize resistant cancer cells to TRAIL. We found that the combination of TRAIL with curcumin can synergistically induces apoptosis in three TRAIL-resistant breast cancer cell lines. The mechanism behind this synergistic cell death was investigated by examining an effect of curcumin on the expression and activation of TRAIL-associated cell death proteins. Immunoblotting, RNA interference, and use of chemical inhibitors of TRAIL-activate signaling revealed differential effects of curcumin on the expression of Mcl-1 and activities of ERK and Akt. Curcumin-induced production of reactive oxygen species did not affect total expression of DR5 but it enhanced mobilization of DR5 to the plasma membrane. In these breast cancer cells curcumin also induced downregulation of IAP proteins. Taken together, our data suggest that a combination of TRAIL and curcumin is a potentially promising treatment for breast cancer, although the specific mechanisms involved in this sensitization could differ even among breast cancer cells of different origins.Molecular and Cellular Biochemistry 07/2013; · 2.33 Impact Factor
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ABSTRACT: The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family of cytokines. TRAIL selectively induces apoptotic cell death in various tumors and cancer cells, but it has little or no toxicity in normal cells. Agonism of TRAIL receptors has been considered to be a valuable cancer-therapeutic strategy. However, more than 85% of primary tumors are resistant to TRAIL, emphasizing the importance of investigating how to overcome TRAIL resistance. In this report, we have found that nemadipine-A, a cell-permeable L-type calcium channel inhibitor, sensitizes TRAIL-resistant cancer cells to this ligand. Combination treatments using TRAIL with nemadipine-A synergistically induced both the caspase cascade and apoptotic cell death, which were blocked by a pan caspase inhibitor (zVAD) but not by autophagy or a necrosis inhibitor. We further found that nemadipine-A, either alone or in combination with TRAIL, notably reduced the expression of survivin, an inhibitor of the apoptosis protein (IAP) family of proteins. Depletion of survivin by small RNA interference (siRNA) resulted in increased cell death and caspase activation by TRAIL treatment. These results suggest that nemadipine-A potentiates TRAIL-induced apoptosis by down-regulation of survivin expression in TRAIL resistant cells. Thus, combination of TRAIL with nemadipine-A may serve a new therapeutic scheme for the treatment of TRAIL resistant cancer cells, suggesting that a detailed study of this combination would be useful.Biomolecules and Therapeutics 01/2013; 21(1):29-34. · 0.79 Impact Factor