Hedgehog inhibition promotes a switch from type II to type I cell death receptor signaling in cancer cells

Satoshi Kurita, Justin L. Mott, Sophie C. Cazanave, Christian D. Fingas, Maria E. Guicciardi, Steve F. Bronk, Lewis R. Roberts, Martin E. Fernandez-Zapico, Gregory J. Gores

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

TRAIL is a promising therapeutic agent for human malignancies. TRAIL often requires mitochondrial dysfunction, referred to as the Type II death receptor pathway, to promote cytotoxicity. However, numerous malignant cells are TRAIL resistant due to inhibition of this mitochondrial pathway. Using cholangiocarcinoma cells as a model of TRAIL resistance, we found that Hedgehog signaling blockade sensitized these cancer cells to TRAIL cytotoxicity independent of mitochondrial dysfunction, referred to as Type I death receptor signaling. This switch in TRAIL requirement from Type II to Type I death receptor signaling was demonstrated by the lack of functional dependence on Bid/Bim and Bax/Bak, proapoptotic components of the mitochondrial pathway. Hedgehog signaling modulated expression of X-linked inhibitor of apoptosis (XIAP), which serves to repress the Type I death receptor pathway. siRNA targeted knockdown of XIAP mimics sensitization to mitochondria-independent TRAIL killing achieved by Hedgehog inhibition. Regulation of XIAP expression by Hedgehog signaling is mediated by the glioma-associated oncogene 2 (GLI2), a downstream transcription factor of Hedgehog. In conclusion, these data provide additional mechanisms modulating cell death by TRAIL and suggest Hedgehog inhibition as a therapeutic approach for TRAIL-resistant neoplasms.

Original languageEnglish (US)
Article numbere18330
JournalPloS one
Volume6
Issue number3
DOIs
StatePublished - Apr 8 2011

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Death Domain Receptors
Erinaceidae
Cell death
cell death
Cell Death
Cells
Switches
Apoptosis
Neoplasms
Cytotoxicity
apoptosis
Cholangiocarcinoma
cytotoxicity
Oncogenes
Mitochondria
Glioma
Small Interfering RNA
therapeutics
Transcription Factors
oncogenes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Kurita, S., Mott, J. L., Cazanave, S. C., Fingas, C. D., Guicciardi, M. E., Bronk, S. F., ... Gores, G. J. (2011). Hedgehog inhibition promotes a switch from type II to type I cell death receptor signaling in cancer cells. PloS one, 6(3), [e18330]. https://doi.org/10.1371/journal.pone.0018330

Hedgehog inhibition promotes a switch from type II to type I cell death receptor signaling in cancer cells. / Kurita, Satoshi; Mott, Justin L.; Cazanave, Sophie C.; Fingas, Christian D.; Guicciardi, Maria E.; Bronk, Steve F.; Roberts, Lewis R.; Fernandez-Zapico, Martin E.; Gores, Gregory J.

In: PloS one, Vol. 6, No. 3, e18330, 08.04.2011.

Research output: Contribution to journalArticle

Kurita, S, Mott, JL, Cazanave, SC, Fingas, CD, Guicciardi, ME, Bronk, SF, Roberts, LR, Fernandez-Zapico, ME & Gores, GJ 2011, 'Hedgehog inhibition promotes a switch from type II to type I cell death receptor signaling in cancer cells', PloS one, vol. 6, no. 3, e18330. https://doi.org/10.1371/journal.pone.0018330
Kurita, Satoshi ; Mott, Justin L. ; Cazanave, Sophie C. ; Fingas, Christian D. ; Guicciardi, Maria E. ; Bronk, Steve F. ; Roberts, Lewis R. ; Fernandez-Zapico, Martin E. ; Gores, Gregory J. / Hedgehog inhibition promotes a switch from type II to type I cell death receptor signaling in cancer cells. In: PloS one. 2011 ; Vol. 6, No. 3.
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