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Cytoprotective effects of IAPs revealed by a small molecule antagonist.

Publication ,  Journal Article
Galbán, S; Hwang, C; Rumble, JM; Oetjen, KA; Wright, CW; Boudreault, A; Durkin, J; Gillard, JW; Jaquith, JB; Morris, SJ; Duckett, CS
Published in: Biochem J
February 1, 2009

Deregulated expression of members of the IAP (inhibitor of apoptosis) family has been identified in a wide variety of neoplastic cells, and synthetic IAP antagonists represent a promising novel class of chemotherapeutic agents. Early work focused on the ability of these compounds to block the caspase-inhibitory function of XIAP (X-linked IAP). However, recent studies have shown that IAP antagonists, although primarily designed to target XIAP, trigger ubiquitin-mediated degradation of two related proteins, c-IAP (cellular IAP) 1 and c-IAP2, and through this process potentiates the death of tumour cells via autocrine cellular-signalling pathways. In this context, the relative contribution of XIAP as a target of this class of compounds is unclear. In the present study, we examine the involvement of XIAP using a recently described synthetic IAP antagonist, AEG40730, and through comparison of a human XIAP-depleted tumour cell line with its isogenic wild-type control line. Treatment with nanomolar concentrations of AEG40730 resulted in the loss of both XIAP and c-IAP1 proteins, albeit with different kinetics. Although XIAP-deficient HCT116 cells retained some sensitivity to external apoptotic stimuli, the results suggest that IAP antagonists, such as AEG40730, exert their apoptosis-enhancing effects through XIAP in addition to the c-IAPs. These results indicate that IAP antagonists can target multiple IAPs to augment distinct pro-apoptotic signalling pathways, thereby revealing the potential for these compounds in cancer therapy and underscoring the promise of IAP-targeted therapies.

Duke Scholars

Published In

Biochem J

DOI

EISSN

1470-8728

Publication Date

February 1, 2009

Volume

417

Issue

3

Start / End Page

765 / 771

Location

England

Related Subject Headings

  • bcl-X Protein
  • bcl-2-Associated X Protein
  • X-Linked Inhibitor of Apoptosis Protein
  • TNF-Related Apoptosis-Inducing Ligand
  • Signal Transduction
  • Inhibitor of Apoptosis Proteins
  • Humans
  • HCT116 Cells
  • Down-Regulation
  • Dipeptides
 

Citation

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MLA
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Galbán, S., Hwang, C., Rumble, J. M., Oetjen, K. A., Wright, C. W., Boudreault, A., … Duckett, C. S. (2009). Cytoprotective effects of IAPs revealed by a small molecule antagonist. Biochem J, 417(3), 765–771. https://doi.org/10.1042/BJ20081677
Galbán, Stefanie, Clara Hwang, Julie M. Rumble, Karolyn A. Oetjen, Casey W. Wright, Alain Boudreault, Jon Durkin, et al. “Cytoprotective effects of IAPs revealed by a small molecule antagonist.Biochem J 417, no. 3 (February 1, 2009): 765–71. https://doi.org/10.1042/BJ20081677.
Galbán S, Hwang C, Rumble JM, Oetjen KA, Wright CW, Boudreault A, et al. Cytoprotective effects of IAPs revealed by a small molecule antagonist. Biochem J. 2009 Feb 1;417(3):765–71.
Galbán, Stefanie, et al. “Cytoprotective effects of IAPs revealed by a small molecule antagonist.Biochem J, vol. 417, no. 3, Feb. 2009, pp. 765–71. Pubmed, doi:10.1042/BJ20081677.
Galbán S, Hwang C, Rumble JM, Oetjen KA, Wright CW, Boudreault A, Durkin J, Gillard JW, Jaquith JB, Morris SJ, Duckett CS. Cytoprotective effects of IAPs revealed by a small molecule antagonist. Biochem J. 2009 Feb 1;417(3):765–771.

Published In

Biochem J

DOI

EISSN

1470-8728

Publication Date

February 1, 2009

Volume

417

Issue

3

Start / End Page

765 / 771

Location

England

Related Subject Headings

  • bcl-X Protein
  • bcl-2-Associated X Protein
  • X-Linked Inhibitor of Apoptosis Protein
  • TNF-Related Apoptosis-Inducing Ligand
  • Signal Transduction
  • Inhibitor of Apoptosis Proteins
  • Humans
  • HCT116 Cells
  • Down-Regulation
  • Dipeptides