Cytoprotective effects of IAPs revealed by a small molecule antagonist

Stefanie Galbán, Clara Hwang, Julie M. Rumble, Karolyn A. Oetjen, Casey Wright, Alain Boudreault, Jon Durkin, John W. Gillard, James B. Jaquith, Stephen J. Morris, Colin S. Duckett

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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 isogenicwild-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 proapoptotic signalling pathways, thereby revealing the potential for these compounds in cancer therapy and underscoring the promise of IAP-targeted therapies.

Original languageEnglish (US)
Pages (from-to)765-771
Number of pages7
JournalBiochemical Journal
Volume417
Issue number3
DOIs
StatePublished - Feb 1 2009
Externally publishedYes

Fingerprint

Apoptosis
Molecules
Inhibitor of Apoptosis Proteins
Tumors
Autocrine Communication
HCT116 Cells
Artificial Cells
Cells
Cell signaling
Caspases
Ubiquitin
Tumor Cell Line
Neoplasms
Cell Death
Degradation
Kinetics
Therapeutics
AEG 40730
Proteins

Keywords

  • Apoptosis
  • Caspase
  • Iinhibitor of apoptosis (IAP)
  • Second mitochondrial-derived activatorof caspase (Smac)
  • Tumour-necrosis-factor-related apoptosis-inducing ligand(TRAIL)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Galbán, S., Hwang, C., Rumble, J. M., Oetjen, K. A., Wright, C., Boudreault, A., ... Duckett, C. S. (2009). Cytoprotective effects of IAPs revealed by a small molecule antagonist. Biochemical Journal, 417(3), 765-771. https://doi.org/10.1042/BJ20081677

Cytoprotective effects of IAPs revealed by a small molecule antagonist. / Galbán, Stefanie; Hwang, Clara; Rumble, Julie M.; Oetjen, Karolyn A.; Wright, Casey; Boudreault, Alain; Durkin, Jon; Gillard, John W.; Jaquith, James B.; Morris, Stephen J.; Duckett, Colin S.

In: Biochemical Journal, Vol. 417, No. 3, 01.02.2009, p. 765-771.

Research output: Contribution to journalArticle

Galbán, S, Hwang, C, Rumble, JM, Oetjen, KA, Wright, C, Boudreault, A, Durkin, J, Gillard, JW, Jaquith, JB, Morris, SJ & Duckett, CS 2009, 'Cytoprotective effects of IAPs revealed by a small molecule antagonist', Biochemical Journal, vol. 417, no. 3, pp. 765-771. https://doi.org/10.1042/BJ20081677
Galbán S, Hwang C, Rumble JM, Oetjen KA, Wright C, Boudreault A et al. Cytoprotective effects of IAPs revealed by a small molecule antagonist. Biochemical Journal. 2009 Feb 1;417(3):765-771. https://doi.org/10.1042/BJ20081677
Galbán, Stefanie ; Hwang, Clara ; Rumble, Julie M. ; Oetjen, Karolyn A. ; Wright, Casey ; Boudreault, Alain ; Durkin, Jon ; Gillard, John W. ; Jaquith, James B. ; Morris, Stephen J. ; Duckett, Colin S. / Cytoprotective effects of IAPs revealed by a small molecule antagonist. In: Biochemical Journal. 2009 ; Vol. 417, No. 3. pp. 765-771.
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