Skip to main content

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

Publication ,  Journal Article
Allensworth, JL; Aird, KM; Aldrich, AJ; Batinic-Haberle, I; Devi, GR
Published in: Mol Cancer Ther
July 2012

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 an SOD mimic, 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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

July 2012

Volume

11

Issue

7

Start / End Page

1518 / 1527

Location

United States

Related Subject Headings

  • X-Linked Inhibitor of Apoptosis Protein
  • TNF-Related Apoptosis-Inducing Ligand
  • Superoxide Dismutase-1
  • Superoxide Dismutase
  • Reactive Oxygen Species
  • Oncology & Carcinogenesis
  • Inflammatory Breast Neoplasms
  • Humans
  • Glutathione
  • Gene Expression
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Allensworth, J. L., Aird, K. M., Aldrich, A. J., Batinic-Haberle, I., & Devi, G. R. (2012). XIAP inhibition and generation of reactive oxygen species enhances TRAIL sensitivity in inflammatory breast cancer cells. Mol Cancer Ther, 11(7), 1518–1527. https://doi.org/10.1158/1535-7163.MCT-11-0787
Allensworth, Jennifer L., Katherine M. Aird, Amy J. Aldrich, Ines Batinic-Haberle, and Gayathri R. Devi. “XIAP inhibition and generation of reactive oxygen species enhances TRAIL sensitivity in inflammatory breast cancer cells.Mol Cancer Ther 11, no. 7 (July 2012): 1518–27. https://doi.org/10.1158/1535-7163.MCT-11-0787.
Allensworth JL, Aird KM, Aldrich AJ, Batinic-Haberle I, Devi GR. XIAP inhibition and generation of reactive oxygen species enhances TRAIL sensitivity in inflammatory breast cancer cells. Mol Cancer Ther. 2012 Jul;11(7):1518–27.
Allensworth, Jennifer L., et al. “XIAP inhibition and generation of reactive oxygen species enhances TRAIL sensitivity in inflammatory breast cancer cells.Mol Cancer Ther, vol. 11, no. 7, July 2012, pp. 1518–27. Pubmed, doi:10.1158/1535-7163.MCT-11-0787.
Allensworth JL, Aird KM, Aldrich AJ, Batinic-Haberle I, Devi GR. XIAP inhibition and generation of reactive oxygen species enhances TRAIL sensitivity in inflammatory breast cancer cells. Mol Cancer Ther. 2012 Jul;11(7):1518–1527.

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

July 2012

Volume

11

Issue

7

Start / End Page

1518 / 1527

Location

United States

Related Subject Headings

  • X-Linked Inhibitor of Apoptosis Protein
  • TNF-Related Apoptosis-Inducing Ligand
  • Superoxide Dismutase-1
  • Superoxide Dismutase
  • Reactive Oxygen Species
  • Oncology & Carcinogenesis
  • Inflammatory Breast Neoplasms
  • Humans
  • Glutathione
  • Gene Expression