Abstract 1697: Pharmacological inhibition of ATM results in mitochondrial biogenesis in AMPK independent manner.

Abstract The gene mutated in Ataxia telangiectasia termed Ataxia Telangiectasia Mutated (ATM) encodes for a Serine/Threonine protein kinase which functions at the core of signalling network responsible for DNA damage recognition and repair. Recent evidence has supported the role of ATM beyond DNA repair and has been shown to function in metabolic regulation and cellular homeostasis. Here, we show that ATM regulates mitochondrial biogenesis in MCF-7 and A549 cancer cell lines. Inhibition of ATM kinase activity with its specific inhibitor KU55933 (KU) both with and without DNA damage by Doxorubicin or Bleomycin resulted in evoked cytosolic Ca2+ ions leading to rapid, but sustained induction of mitochondrial biogenesis in these cell lines. This induction was independent of AMPK, a kinase previously shown to be involved in mitochondrial biogenesis as KU treatment resulted in downregulation of phospho AMPK. Moreover siRNA mediated knockdown of AMPK could not prevent KU dependent induction of mitochondrial biogenesis. Interestingly, KU treatment resulted in induction of Extracellular signal-regulated kinase(ERK) and CREB phosphorylation. Inhibition of ERK signalling by using MEK inhibitor U0126 disrupted KU dependent induction of mitochondrial biogenesis demonstrating the involvement of ERK signalling cascade in mitochondrial biogenesis upon ATM or AMPK inhibition. These results demonstrate that ATM maintains cellular homeostasis by regulating AMPK mediated mitochondrial biogenesis and that perturbation in this pathway by KU treatment causes a switch in mitochondrial biogenesis in ERK dependent manner. This study indicates cancer cell's fail-safe mechanism in maintaining its homeostasis by up-regulating mitochondrial biogenesis upon inhibition of ATM. Citation Format: Hilal S. Khalil, Hemanth Tummala, Laura DeCaris, Nikolai Zhelev. Pharmacological inhibition of ATM results in mitochondrial biogenesis in AMPK independent manner. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1697. doi:10.1158/1538-7445.AM2013-1697