Tudor staphylococcal nuclease drives chemoresistance of non-small cell lung carcinoma cells by regulating S100A11
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Anna Zagryazhskaya1, Olga Surova1,2, Nadeem S. Akbar1, Giulia Allavena1,3, Katarina Gyuraszova1,4, Irina B. Zborovskaya5,6, Elena M. Tchevkina5,6, Boris Zhivotovsky1,6
1Institute of Environmental Medicine, Division of Toxicology, Stockholm, Sweden
2Ludwig Institute for Cancer Research Ltd, Karolinska Institutet, Stockholm, Sweden
3Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
4Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Šafárik University in Košice, Košice, Slovakia
5NN Blokhin Russian Cancer Research Center, Moscow, Russia
6Faculty of Fundamental Medicine, ML Lomonosov State University, Moscow, Russia
Boris Zhivotovsky, e-mail: Boris.Zhivotovsky@ki.se
Keywords: tudor staphylococcal nuclease, S100A11, phospholipase A2, non-small cell lung cancer, apoptosis
Received: December 19, 2014 Accepted: March 07, 2015 Published: March 26, 2015
Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC), the major lung cancer subtype, is characterized by high resistance to chemotherapy. Here we demonstrate that Tudor staphylococcal nuclease (SND1 or TSN) is overexpressed in NSCLC cell lines and tissues, and is important for maintaining NSCLC chemoresistance. Downregulation of TSN by RNAi in NSCLC cells led to strong potentiation of cell death in response to cisplatin. Silencing of TSN was accompanied by a significant decrease in S100A11 expression at both mRNA and protein level. Downregulation of S100A11 by RNAi resulted in enhanced sensitivity of NSCLC cells to cisplatin, oxaliplatin and 5-fluouracil. AACOCF3, a phospholipase A2 (PLA2) inhibitor, strongly abrogated chemosensitization upon silencing of S100A11 suggesting that PLA2 inhibition by S100A11 governs the chemoresistance of NSCLC. Moreover, silencing of S100A11 stimulated mitochondrial superoxide production, which was decreased by AACOCF3, as well as N-acetyl-L-cysteine, which also mimicked the effect of PLA2 inhibitor on NSCLC chemosensitization upon S100A11 silencing. Thus, we present the novel TSN-S100A11-PLA2 axis regulating superoxide-dependent apoptosis, triggered by platinum-based chemotherapeutic agents in NSCLC that may be targeted by innovative cancer therapies.
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