Overcoming cancer cell resistance to Smac mimetic induced apoptosis by modulating cIAP-2 expression

Sean L. Petersen, Michael Peyton, John D. Minna, Xiaodong Wang

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Smac mimetics target cancer cells in a TNFα-dependent manner, partly via proteasome degradation of cellular inhibitor of apoptosis 1 (cIAP1) and cIAP2. Degradation of cIAPs triggers the release of receptor interacting protein kinase (RIPK1) from TNF receptor I (TNFR1) to form a caspase-8 activating complex together with the adaptor protein Fas-associated death domain (FADD). We report here a means through which cancer cells mediate resistance to Smac mimetic/TNFα-induced apoptosis and corresponding strategies to overcome such resistance. These human cancer cell lines evades Smac mimetic-induced apoptosis by up-regulation of cIAP2, which although initially degraded, rebounds and is refractory to subsequent degradation. cIAP2 is induced by TNFα via NF-κB and modulation of the NF-κB signal renders otherwise resistant cells sensitive to Smac mimetics. In addition, other signaling pathways, including phosphatidyl inositol-3 kinase (PI3K), have the potential to concurrently regulate cIAP2. Using the PI3K inhibitor, LY294002, cIAP2 up-regulation was suppressed and resistance to Smac mimetics-induced apoptosis was also overcome.

Original languageEnglish (US)
Pages (from-to)11936-11941
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number26
DOIs
StatePublished - Jun 29 2010

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Apoptosis
Phosphatidylinositols
Neoplasms
Phosphotransferases
Up-Regulation
Fas-Associated Death Domain Protein
Receptor-Interacting Protein Serine-Threonine Kinases
Receptors, Tumor Necrosis Factor, Type I
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Caspase 8
Tumor Necrosis Factor Receptors
Proteasome Endopeptidase Complex
Protein Kinases
Cell Line
aposome

Keywords

  • Caspase-8
  • NF-κB
  • PI3K
  • PRIK1
  • TNFα

ASJC Scopus subject areas

  • General

Cite this

Overcoming cancer cell resistance to Smac mimetic induced apoptosis by modulating cIAP-2 expression. / Petersen, Sean L.; Peyton, Michael; Minna, John D.; Wang, Xiaodong.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 26, 29.06.2010, p. 11936-11941.

Research output: Contribution to journalArticle

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