Molecular & Cellular Toxicology

The Korean Society of Toxicogenomics and Toxicoproteomics (대한독성유전 단백체학회)
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DNA Bis-intercalating Agent, Echinomycin-induced Apoptosis via Bcl-2 Dependence Pathway in Human Colon Cancer Cells

  • Park, Ju-Youn (Department of Microbiology, Yonsei University Wonju College of Medicine) ;
  • Ryang, Yong-Suk (Department of Biomedical Laboratory Science, College of Health Science, Yonsei University) ;
  • Kim, Jong-Bae (Department of Biomedical Laboratory Science, College of Health Science, Yonsei University) ;
  • Chang, Jae-Ho (Institute of Lifelong Health, Institute of Basic Medical Science, Yonsei University Wonju College of Medicine) ;
  • Cho, Hyeon-Cheol (Department of Microbiology, Yonsei University Wonju College of Medicine) ;
  • Kim, Soo-Ki (Department of Microbiology, Yonsei University Wonju College of Medicine)
  • Published : 2008.06.30
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Abstract

Despite versatile activity (cancericidal, antimicrobial, hypoxia inducible factor (HIF) inhibition, immune deactivation of DNA bis-intercalation agent, echinomycin, its specific mechanism has been elusive. Of these novel mechanisms, we reported that using human colon cancer cells (HT-29), apoptotic machinery induced by echinomycin might be dependent of caspase-3 pathway. Despite a partial enlightenment of prototypic signal path triggered by echinomycin, the role of Bcl-2 in this signaling pathway is unclear. To address this issue, we explored whether or not echinomycin would overcome the anti-apoptotic impact of Bcl-2 in HT-29 cells by the controlled Bcl-2 overexpression. Prior to this proof, we confirmed that echinomycin induces mitochondrial depolarization, then triggering the mitochondrial pathway of apoptosis with an involvement of upstream cas-pases-3. Transiently transfection with inactive Bax-DNA failed to prevent echinomycin-induced apoptosis in HT-29 cells. To dissect the role of Bcl-2 in echinomycin-induced apoptosis, HT-29 cells were transiently transfected with Bcl-2 DNA for overexpression and then treated with echinomycin for 24h. Combined analyses of DNA fragmentation and flow cytometric analysis clearly verified that echinomycin-induced apoptosis was drastically attenuated by Bcl-2 overexpression, whereas a control vector rarely affected echinomycin-induced apoptosis. Collectively, these data verify that Bcl-2 regulates echinomycin-induced apoptosis in HT-29 cells. To my knowledge, this is the first evidence that of diverse, structured minor groove binders (MGB), the prototypic echinomycin might control the apoptotic signaling via Bcl-2-mitochondrial pathway.

Keywords

References

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