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ATM kinase activity modulates cFLIP protein levels: potential interplay between DNA damage signalling and

Venturina Stagni1, Michele Mingardi, Simonetta Santini

  • 1Laboratory of Cell Signaling, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy.

Carcinogenesis
|September 30, 2010
PubMed

Insights

Ataxia telangiectasia mutated (ATM) kinase activity is crucial for down-regulating cFLIP proteins following DNA damage, enhancing cancer cells

Area of Science:

  • Molecular Biology
  • Cancer Therapy
  • Cell Death Signaling

Background:

  • Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) shows promise for cancer therapy, but many cancers exhibit resistance.
  • cFLIP proteins inhibit TRAIL-induced apoptosis and are often overexpressed in cancers, making them a target for sensitization strategies.
  • DNA-damaging agents like 5-fluorouracil (5-FU) can down-regulate cFLIP, but the underlying mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the role of Ataxia Telangiectasia Mutated (ATM) kinase in the down-regulation of cFLIP proteins upon DNA damage.
  • To determine if ATM activity is required for DNA-damaging agents to sensitize hepatocellular carcinoma (HCC) cells to TRAIL.
  • To elucidate the molecular mechanisms by which ATM influences cFLIP levels and TRAIL sensitivity.

Main Methods:

  • Genetic evidence was used to assess the requirement of ATM kinase activity.
  • Hepatocellular carcinoma (HCC) cell lines were treated with DNA-damaging agents (5-FU, neocarzinostatin).
  • cFLIP protein levels, ubiquitination, and sensitivity to TRAIL were analyzed in response to DNA damage and ATM activity.

Main Results:

  • ATM kinase activity is essential for the down-regulation of both cFLIP(L) and cFLIP(S) isoforms induced by 5-FU and neocarzinostatin.
  • ATM-mediated cFLIP down-regulation sensitizes HCC cell lines to TRAIL-induced apoptosis.
  • ATM enhances cFLIP(L) ubiquitination in response to DNA damage, independent of p53.

Conclusions:

  • ATM kinase acts as a critical mediator linking DNA damage response pathways with death receptor signaling.
  • ATM activity is required for sensitizing cancer cells to TRAIL via DNA-damaging agents.
  • The expression of functional ATM in tumor cells may be vital for the success of combined TRAIL-based and DNA-damaging therapies.

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