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Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen
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Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen

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Induction of the apoptosis inhibitor ARC by Ras in human cancers

Lily Wu1, Young-Jae Nam, Gloria Kung

  • 1Department of Medicine, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

The Journal of Biological Chemistry
|April 16, 2010
PubMed

Insights

Ras signaling pathways activate apoptosis repressor with caspase recruitment domain (ARC) in epithelial cancers. ARC promotes cancer cell survival and proliferation, highlighting its role in oncogenesis.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Signaling

Background:

  • Apoptosis inhibition is crucial for cancer development.
  • Apoptosis repressor with caspase recruitment domain (ARC) inhibits programmed cell death pathways.
  • ARC is upregulated in epithelial cancers, conferring resistance to cell death.

Purpose of the Study:

  • To investigate the mechanisms regulating ARC induction in cancer.
  • To determine the role of Ras signaling in ARC expression and function.
  • To elucidate ARC's contribution to Ras-mediated oncogenesis.

Main Methods:

  • Overexpression of activated Ras (N-Ras, H-Ras) in cell lines.
  • Transgenic mouse models with activated H-Ras.
  • Knockdown of endogenous N-Ras in cancer cells.
  • Analysis of ARC mRNA and protein levels.
  • Luciferase reporter assays to assess promoter activity.
  • Ubiquitination and proteasomal degradation assays.

Main Results:

  • Ras activation (N-Ras, H-Ras) increases ARC mRNA and protein levels via transcriptional activation and enhanced protein stability.
  • Ras signaling upregulates ARC in normal mammary epithelium and in Ras-induced tumors.
  • N-Ras knockdown reduces ARC levels in breast and colon cancer cells.
  • Ras stabilizes ARC protein by inhibiting its polyubiquitination and proteasomal degradation.
  • ARC mediates Ras-induced cell survival and cell cycle progression.

Conclusions:

  • Ras signaling is a key driver of ARC induction in epithelial cancers.
  • ARC contributes to the pro-survival and proliferative effects of Ras in cancer.
  • Targeting the Ras-ARC axis may offer therapeutic strategies for epithelial cancers.

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