Related Experiment Video

Updated: Mar 8, 2026

Generation of a RIP1 Knockout U937 Cell Line Using the CRISPR-Cas9 System
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Generation of a RIP1 Knockout U937 Cell Line Using the CRISPR-Cas9 System

Published on: April 11, 2025

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TNF Signaling through RIP1 Kinase Enhances SN38-Induced Death in Colon Adenocarcinoma

Lucia Cabal-Hierro1, Peter J O'Dwyer2

  • 1Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. Lucia_Cabal-Hierro@dfci.harvard.edu.

Molecular Cancer Research : MCR
|January 15, 2017
PubMed

Insights

Tumor necrosis factor (TNF) enhances the effectiveness of chemotherapy drugs like SN38 in colorectal cancer. Receptor-interacting protein kinase 1 (RIPK1) is crucial for this enhanced cell death and tumor growth inhibition.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Receptor-interacting protein kinases 1 and 3 (RIPK1/RIP3) are key components of the necrosome complex, influencing cell fate in TNF signaling.
  • The role of TNF signaling in mediating the cytotoxic effects of DNA-damaging agents in colorectal cancer remains incompletely understood.

Purpose of the Study:

  • To investigate the role of TNF signaling in the cytotoxic action of DNA-damaging agents in colon cancer cells.
  • To determine the involvement of RIPK1 and RIPK3 in TNF-mediated sensitization to chemotherapy.

Main Methods:

  • Treatment of colon cancer cell lines with DNA-damaging agents (including SN38) alone and in combination with TNF.
  • Analysis of RIPK1 and RIPK3 levels following drug treatment.
  • Assessment of tumor growth inhibition in a xenograft model with RIPK1 downregulation.

Main Results:

  • Combination of TNF with DNA-damaging agents, particularly SN38, increased cancer cell sensitivity and induced cell death.
  • Changes in RIPK1 and RIPK3 levels were observed with SN38 monotherapy or combination therapy.
  • Downregulation of RIPK1 led to increased resistance to SN38 and impaired tumor growth inhibition in vivo.

Conclusions:

  • TNF plays a critical role in enhancing the cytotoxic efficacy of SN38 in colorectal cancer.
  • RIPK1 is essential for mediating SN38 cytotoxicity via the TNF/TNFR signaling pathway.
  • RIPK1 may serve as a biomarker for predicting clinical outcomes of irinotecan (SN38) treatment and suggests potential for TNF-based therapies.

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