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ROS-PIASγ cross talk channelizes ATM signaling from resistance to apoptosis during chemosensitization of resistant

S Mohanty1, S Saha1, D Md S Hossain1

  • 1Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VII M, Kolkata 700 054, India.

Cell Death & Disease
|January 25, 2014
PubMed

Insights

Tumor redox status controls ATM

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • ATM kinase is crucial in DNA damage response and therapeutic resistance.
  • The molecular mechanisms governing ATM's switch between chemoresistance and chemosensitivity remain unclear.
  • Tumor redox status, particularly reactive oxygen species (ROS), is implicated in cancer progression and treatment response.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which tumor redox status influences ATM-mediated chemoresistance and chemosensitivity.
  • To identify key regulators of the ATM signaling pathway in response to genotoxic stress and varying ROS levels.
  • To explore the role of PIASγ in modulating ATM's function in drug-resistant tumors.

Main Methods:

  • In vitro cell culture experiments assessing ATM signaling, apoptosis, and protein modifications (sumoylation, ubiquitination).
  • Genomic manipulation (knockout and overexpression) of PIASγ in tumor cell lines and allograft mouse models.
  • Measurement of reactive oxygen species (ROS) levels and their impact on key protein interactions (ATM/IKKγ, PIASγ/IKKγ).

Main Results:

  • Low ROS conditions promote ATM/sumoylated-IKKγ interaction, leading to NFκB activation and resistance to JNK-mediated apoptosis.
  • Elevated ROS restores ATM/JNK pro-apoptotic signaling by inducing PIASγ oxidation and degradation, disrupting NFκB activation.
  • PIASγ knockout tumors showed reduced resistance under low ROS, while PIASγ overexpression inhibited apoptosis in high ROS conditions.
  • In vivo studies confirmed that PIASγ modulates ATM-dependent chemoresistance, correlating with tumor ROS levels.

Conclusions:

  • Cellular ROS levels act as a critical determinant of ATM's role in chemosensitivity versus chemoresistance.
  • PIASγ is a key mediator, linking cellular ROS to ATM signaling and NFκB-mediated drug resistance.
  • Targeting PIASγ and upregulating ROS may represent a novel therapeutic strategy to overcome NFκB-driven tumor drug resistance.

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