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Tudor staphylococcal nuclease drives chemoresistance of non-small cell lung carcinoma cells by regulating S100A11.

Zagryazhskaya A, Surova O, Akbar NS, Allavena G, Gyuraszova K, Zborovskaya IB, Tchevkina EM, Zhivotovsky B - Oncotarget (2015)

Bottom Line: Lung cancer is the leading cause of cancer-related deaths worldwide.Silencing of TSN was accompanied by a significant decrease in S100A11 expression at both mRNA and protein level.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Environmental Medicine, Division of Toxicology, Stockholm, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus

Silencing of TSN and S100A11 differently affects autophagy in NSCLC cellsA, B. p62 accumulation and LC3 lipidation in A549 cells treated as indicated. GAPDH was used as loading control. For details see “Materials and Methods” section. The data are representative of three independent experiments.
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Figure 4: Silencing of TSN and S100A11 differently affects autophagy in NSCLC cellsA, B. p62 accumulation and LC3 lipidation in A549 cells treated as indicated. GAPDH was used as loading control. For details see “Materials and Methods” section. The data are representative of three independent experiments.

Mentions: Autophagy, a catabolic process regulating turnover of organelles and macromolecules, may promote cell death or preserve cell survival, depending on physiological context [24]. Interestingly, autophagy was not affected by silencing of S100A11 but was significantly suppressed by silencing of TSN, as assessed by LC3 lipidation and p62 accumulation in A549 cells (Fig. 4A). These data were further confirmed by assessment of autophagic flux using Bafilomycin A (Baf A) (Fig. 4B). Therefore, autophagy seems not to be involved in chemosensitization observed upon downregulation of S100A11, while widespread transcriptional changes observed upon TSN silencing may account for an additional role of TSN in autophagy regulation.


Tudor staphylococcal nuclease drives chemoresistance of non-small cell lung carcinoma cells by regulating S100A11.

Zagryazhskaya A, Surova O, Akbar NS, Allavena G, Gyuraszova K, Zborovskaya IB, Tchevkina EM, Zhivotovsky B - Oncotarget (2015)

Silencing of TSN and S100A11 differently affects autophagy in NSCLC cellsA, B. p62 accumulation and LC3 lipidation in A549 cells treated as indicated. GAPDH was used as loading control. For details see “Materials and Methods” section. The data are representative of three independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494929&req=5

Figure 4: Silencing of TSN and S100A11 differently affects autophagy in NSCLC cellsA, B. p62 accumulation and LC3 lipidation in A549 cells treated as indicated. GAPDH was used as loading control. For details see “Materials and Methods” section. The data are representative of three independent experiments.
Mentions: Autophagy, a catabolic process regulating turnover of organelles and macromolecules, may promote cell death or preserve cell survival, depending on physiological context [24]. Interestingly, autophagy was not affected by silencing of S100A11 but was significantly suppressed by silencing of TSN, as assessed by LC3 lipidation and p62 accumulation in A549 cells (Fig. 4A). These data were further confirmed by assessment of autophagic flux using Bafilomycin A (Baf A) (Fig. 4B). Therefore, autophagy seems not to be involved in chemosensitization observed upon downregulation of S100A11, while widespread transcriptional changes observed upon TSN silencing may account for an additional role of TSN in autophagy regulation.

Bottom Line: Lung cancer is the leading cause of cancer-related deaths worldwide.Silencing of TSN was accompanied by a significant decrease in S100A11 expression at both mRNA and protein level.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Environmental Medicine, Division of Toxicology, Stockholm, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus