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

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Quantitative PCR-based Assay to Measure Sonic Hedgehog Signaling in Cellular Model of Ciliogenesis
07:26

Quantitative PCR-based Assay to Measure Sonic Hedgehog Signaling in Cellular Model of Ciliogenesis

Published on: January 31, 2025

Satoshi Kurita1, Justin L Mott, Sophie C Cazanave

  • 1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States of America.

Plos One
|April 13, 2011
PubMed

Insights

Hedgehog signaling blockade sensitizes resistant cancer cells to TRAIL therapy by shifting cell death signaling. This approach bypasses mitochondrial pathways, offering a new strategy for treating TRAIL-resistant neoplasms.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise for cancer treatment.
  • TRAIL-induced cancer cell death often relies on mitochondrial pathways (Type II), but resistance emerges via mitochondrial pathway inhibition.
  • Malignant cells can be resistant to TRAIL due to these mitochondrial pathway disruptions.

Purpose of the Study:

  • To investigate mechanisms of TRAIL resistance in cholangiocarcinoma.
  • To determine if targeting Hedgehog signaling can overcome TRAIL resistance.
  • To elucidate the signaling pathways involved in TRAIL sensitization.

Main Methods:

  • Utilized cholangiocarcinoma cells as a model for TRAIL resistance.
  • Investigated the role of Hedgehog signaling blockade in TRAIL-induced cytotoxicity.
  • Assessed the dependence on mitochondrial pathway components (Bid/Bim, Bax/Bak) and Type I death receptor signaling.
  • Examined the modulation of X-linked inhibitor of apoptosis (XIAP) expression by Hedgehog signaling.
  • Employed siRNA to knockdown XIAP and assess its effect on TRAIL sensitivity.
  • Investigated the role of glioma-associated oncogene 2 (GLI2) in regulating XIAP.

Main Results:

  • Hedgehog signaling blockade sensitized TRAIL-resistant cholangiocarcinoma cells to TRAIL.
  • Sensitization occurred independently of mitochondrial dysfunction, indicating a switch to Type I death receptor signaling.
  • This switch was confirmed by the lack of dependence on Bid/Bim and Bax/Bak.
  • Hedgehog signaling was found to modulate XIAP expression, a repressor of the Type I pathway.
  • XIAP knockdown mimicked the sensitization effect of Hedgehog inhibition.
  • Glioma-associated oncogene 2 (GLI2) was identified as the mediator of Hedgehog signaling's regulation of XIAP.

Conclusions:

  • Hedgehog signaling blockade offers a novel therapeutic strategy to overcome TRAIL resistance in cancer.
  • The mechanism involves a switch from TRAIL-dependent Type II to Type I death receptor signaling.
  • Modulation of XIAP by Hedgehog signaling, via GLI2, is a key factor in this sensitization process.
  • These findings provide new insights into TRAIL-mediated cell death and suggest therapeutic avenues for resistant cancers.

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