XIAP inhibition and generation of reactive oxygen species enhances TRAIL sensitivity in inflammatory breast cancer cells

Jennifer L. Allensworth, Katherine M. Aird, Amy J. Aldrich, Ines Batinic-Haberle, Gayathri R. Devi

Research output: Contribution to journalArticle

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Abstract

We recently identified superoxide dismutase (SOD) overexpression and decreased induction of reactive oxygen species (ROS)-mediated apoptosis in models of inflammatory breast cancer (IBC) cells with acquired therapeutic resistance. This population of cells has high expression of X-linked inhibitor of apoptosis protein (XIAP), which inhibits both extrinsic and intrinsic apoptosis pathways. We therefore wanted to evaluate the effect of classical apoptosis-inducing agent TRAIL, a proapoptotic receptor agonist that selectively triggers death receptor (DR)-mediated apoptosis in cancer cells, in the IBC acquired resistance model. XIAP levels and subsequent inhibition of caspase activity inversely correlated with TRAIL sensitivity in our models of IBC. These include SUM149, a basal-type cell line isolated from primary IBC tumors and isogenic SUM149-derived lines rSUM149 and SUM149 wtXIAP, models of acquired therapeutic resistance with endogenous and exogenous XIAP overexpression, respectively. Inhibition of XIAP function using embelin, a plant-derived cell permeable small molecule, in combination with TRAIL caused a synergistic decrease in cell viability. Embelin treatment resulted in activation of extracellular signal-regulated kinase (ERK)1/2 and ROS accumulation, which correlated with downregulation of antioxidant protein SOD1 and consumption of redox modulator reduced glutathione in the XIAP-overexpressing cells. Simultaneous treatment with anSODmimic, which protects against ROS accumulation, reversed the decrease in cell viability caused by embelin + TRAIL treatment. Embelin primes IBC cells for TRAIL-mediated apoptosis by its direct action on the anti-caspase activity of XIAP and by shifting the cellular redox balance toward oxidative stress-mediated apoptosis. Thus, ROS modulators represent a novel approach to enhance efficacy of TRAIL-based treatment protocols in IBC.

Original languageEnglish (US)
Pages (from-to)1518-1527
Number of pages10
JournalMolecular cancer therapeutics
Volume11
Issue number7
DOIs
StatePublished - Jul 1 2012

Fingerprint

X-Linked Inhibitor of Apoptosis Protein
Inflammatory Breast Neoplasms
Reactive Oxygen Species
Apoptosis
Caspases
Oxidation-Reduction
Cell Survival
Therapeutics
Death Domain Receptors
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Plant Cells
Clinical Protocols
Superoxide Dismutase
Glutathione
Oxidative Stress
Down-Regulation
Antioxidants
Breast Neoplasms
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Allensworth, Jennifer L. ; Aird, Katherine M. ; Aldrich, Amy J. ; Batinic-Haberle, Ines ; Devi, Gayathri R. / XIAP inhibition and generation of reactive oxygen species enhances TRAIL sensitivity in inflammatory breast cancer cells. In: Molecular cancer therapeutics. 2012 ; Vol. 11, No. 7. pp. 1518-1527.
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XIAP inhibition and generation of reactive oxygen species enhances TRAIL sensitivity in inflammatory breast cancer cells. / Allensworth, Jennifer L.; Aird, Katherine M.; Aldrich, Amy J.; Batinic-Haberle, Ines; Devi, Gayathri R.

In: Molecular cancer therapeutics, Vol. 11, No. 7, 01.07.2012, p. 1518-1527.

Research output: Contribution to journalArticle

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