Abstract
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. AACOCF(3), a phospholipase A(2) (PLA(2)) inhibitor, strongly abrogated chemosensitization upon silencing of S100A11 suggesting that PLA(2) inhibition by S100A11 governs the chemoresistance of NSCLC. Moreover, silencing of S100A11 stimulated mitochondrial superoxide production, which was decreased by AACOCF(3), as well as N-acetyl-L-cysteine, which also mimicked the effect of PLA(2) inhibitor on NSCLC chemosensitization upon S100A11 silencing. Thus, we present the novel TSN-S100A11-PLA(2) axis regulating superoxide-dependent apoptosis, triggered by platinum-based chemotherapeutic agents in NSCLC that may be targeted by innovative cancer therapies.
Highlights
Lung cancer (LC) is the leading cause of cancerrelated deaths worldwide
We demonstrate that TSN contributes to Non-small cell lung cancer (NSCLC) chemoresistance by facilitating the expression of S100A11, which in turn inhibits phospholipase A2, leading to a decrease in mitochondrial superoxide production, suppressing mitochondrial superoxide-dependent apoptotic cell death
In order to investigate the expression of TSN in lung cancer cells, the level of protein expression was assessed in a panel of NSCLC cell lines (H661, A549, U1810 and H23), in normal lung fibroblasts AG06814 (Fig. 1A) and in clinical samples
Summary
Lung cancer (LC) is the leading cause of cancerrelated deaths worldwide (http://globocan.iarc.fr). Despite improvements in the efficacy of therapeutics, the overall five-year survival rate for lung cancer still hovers around. The initial response to therapy is different among distinct forms of lung cancer. NSCLCs exhibit poor response even in the initial stage, and complete remission, concomitant with a higher degree of resistance to anticancer therapies, is rare. Accumulating data suggest that various treatments used to cure cancer usually inflict DNA damage and trigger apoptotic cell death response [2]. Tumorigenic cells may increase DNA repair capacity as well as deregulate cell survival and apoptotic signaling circuits to impede proper therapy response. Since overall defects in www.impactjournals.com/oncotarget apoptosis have been attributed as being prerequisite for cancer development [3], improved understanding of the targets and limiting factors that can affect tumor resistance are of higher importance for developing therapeutic efficacy to combat cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
