ROS-PIASγ cross talk channelizes ATM signaling from resistance to apoptosis during chemosensitization of resistant tumors.
With the existing knowledge of ATM's role in therapeutic resistance, the present study aimed at identifying the molecular mechanisms that influence ATM to oscillate between chemoresistance and chemosensitivity. We observed that the redox status of tumors functions as a major determinant of ATM-dependent 'resistance-to-apoptosis' molecular switch. At a low reactive oxygen species (ROS) condition during genotoxic insult, the ATM/sumoylated-IKKγ interaction induced NFκB activation that resisted JNK-mediated apoptosis, whereas increasing cellular ROS restored ATM/JNK apoptotic signaling. A search for the upstream missing link revealed that high ROS induces oxidation and ubiquitin-mediated degradation of PIASγ, thereby disrupting PIASγ-IKKγ cross talk, a pre-requisite for IKKγ sumoylation and subsequent NFκB activation. Interruption in the PIASγ-mediated resistance pathway channels ATM signaling toward ATM/JNK pro-death circuitry. These in vitro results also translated to sensitive and resistant tumor allograft mouse models in which low ROS-induced resistance was over-ruled in PIASγ knockout tumors, while its overexpression inhibited high ROS-dependent apoptotic cues. Cumulatively, our findings identified an unappreciated yet critical combinatorial function of cellular ROS and PIASγ in regulating ATM-mediated chemosensitization of resistant tumors. Thus, therapeutic strategies employing ROS upregulation to inhibit PIASγ during genotoxic therapy may, in future, help to eliminate the problems of NFκB-mediated tumor drug resistance.
Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VII M, Kolkata 700 054, India.
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Mohanty
Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VII M, Kolkata 700 054, India.
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Saha
Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VII M, Kolkata 700 054, India.
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Md S Hossain
Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VII M, Kolkata 700 054, India.
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Adhikary
Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VII M, Kolkata 700 054, India.
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Mukherjee
Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VII M, Kolkata 700 054, India.
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Manna
Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VII M, Kolkata 700 054, India.
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Chakraborty
Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VII M, Kolkata 700 054, India.
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Mazumdar
Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VII M, Kolkata 700 054, India.
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Ray
Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VII M, Kolkata 700 054, India.
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Das
Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VII M, Kolkata 700 054, India.
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Chakraborty
Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VII M, Kolkata 700 054, India.
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Sa
Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VII M, Kolkata 700 054, India.
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Das
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D058207:Sumoylation
D000970:Antineoplastic Agents; D016328:NF-kappa B; C485891:PIAS4 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D050828:Protein Inhibitors of Activated STAT; D017382:Reactive Oxygen Species; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051550:I-kappa B Kinase