Author:
Fandy Tamer E,Shankar Sharmila,Srivastava Rakesh K
Abstract
Abstract
Background
Drug resistance is a major concern in cancer therapy. Here, we investigate the clinical potential of the second mitochondria-derived activator of caspase (Smac/DIABLO) in enhancing the apoptosis-inducing potential of commonly used anticancer drugs (paclitaxel, doxorubicin, etoposide, tamoxifen), irradiation and TRAIL in breast carcinoma.
Methods
Breast cancer cells were overexpressed with Smac/DIABLO gene (full-length or Δ55 Smac/DIABLO) or treated with Smac/DIABLO peptide to enhance the apoptosis-inducing potential of chemotherapeutic drugs and irradiation, and sensitize TRAIL-resistant cells. Cell viability and apoptosis were measured by XTT assay and DAPI staining, respectively. Protein-protein interaction was determined by immunoprecipitation followed by the Western blot analysis.
Results
Overexpression of Smac/DIABLO gene (full-length or Δ55 Smac/DIABLO) or treatment with Smac/DIABLO peptide enhances apoptosis induced by paclitaxel, doxorubicin, etoposide, tamoxifen, and irradiation in breast cancer cells. Overexpression of Smac/DIABLO resulted in an increased interaction of Smac/DIABLO with IAPs, which correlated with an increase in caspase-3 activity and apoptosis. Furthermore, Smac/DIABLO sensitized TRAIL-resistant breast cancer cell lines to undergo apoptosis through caspase-3 activation. These data suggest that apoptotic events down-stream of mitochondria were intact in TRAIL-resistant cells since ectopic expression of Smac/DIABLO or pretreatment of cells with Smac/DIABLO peptide completely restored TRAIL sensitivity.
Conclusion
The ability of Smac/DIABLO agonists to enhance the apoptosis-inducing potential of chemotherapeutic drugs and irradiation, and sensitize TRAIL-resistant tumor cells suggests that Smac/DIABLO may induce fundamental alterations in cell signaling pathways. Thus, Smac/DIABLO agonists can be used as promising new candidates for cancer treatment by potentiating cytotoxic therapies.
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology,Molecular Medicine
Reference32 articles.
1. Thornberry NA: The caspase family of cysteine proteases. Br Med Bull. 1997, 53: 478-490.
2. Shankar S, Srivastava RK: Enhancement of therapeutic potential of TRAIL by cancer chemotherapy and irradiation: mechanisms and clinical implications. Drug Resist Updat. 2004, 7: 139-156.
3. Li H, Zhu H, Xu CJ, Yuan J: Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 1998, 94: 491-501.
4. Deveraux QL, Reed JC: IAP family proteins – suppressors of apoptosis. Genes Dev. 1999, 13: 239-252.
5. Kandasamy K, Srinivasula SM, Alnemri ES, Thompson CB, Korsmeyer SJ, Bryant JL, Srivastava RK: Involvement of Proapoptotic Molecules Bax and Bak in Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-induced Mitochondrial Disruption and Apoptosis: Differential Regulation of Cytochrome c and Smac/DIABLO Release. Cancer Res. 2003, 63: 1712-1721.
Cited by
64 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献