Lung cancer cell invasion and expression of intercellular adhesion molecule-1 (ICAM-1) are attenuated by secretory phospholipase A2 inhibition

Yu, Jessica A.; Sadaria, Miral R.; Meng, Xianzhong; Mitra, Sanchayita; Ao, Lihua; Fullerton, David A.; Weyant, Michael J.

doi:10.1016/j.jtcvs.2011.10.026

Cited by 39 publications

(30 citation statements)

References 20 publications

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“…23 Previous work has shown that pharmacologic inhibition of sPLA2 IIA reduces ICAM-1 associated invasion in vitro. 4 On review of the histology, intravascular invasion was noted in the wild-type tumors but not in the knockdown tumors. Further studies will better address the role of sPLA2 IIa in metastatic disease in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…1-4 We previously demonstrated that inhibition of group IIa sPLA2 decreased intercellular adhesion molecule-1 (ICAM-1) associated invasion of lung cancer cells in vitro 4 ; however, the role of the enzyme in lung cancer cell growth has yet to be fully explored.…”

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confidence: 99%

“…16 Evidence suggests that sPLA2 IIa modulates NF- κ B, as ICAM-1 and sPLA2 IIa, both NF- κ B target genes, are downregulated when sPLA2 IIa is inhibited. 3,4,12 …”

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confidence: 99%

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Knockdown of secretory phospholipase A2 IIa reduces lung cancer growth in vitro and in vivo

Mauchley

et al. 2012

The Journal of Thoracic and Cardiovascular Surgery

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Objective Group IIa secretory phospholipase A2 (sPLA2 IIa) plays a role in the malignant potential of several epithelial cancers. Nuclear factor kappa B (NF-κB) regulates cancer cell growth and is modulated by phospholipase activity in many cancer cells. We hypothesized that knockdown of sPLA2 in lung cancer cells would reduce cell proliferation and NF-κB activity in vitro and attenuate tumor growth in vivo. Methods Two human non–small cell lung cancer cell lines (A549 and H358) were transduced with short hairpin RNA targeting sPLA2 group IIa. Quantitative reverse transcriptase-polymerase chain reaction and immunoblotting confirmed knockdown of sPLA2 IIa messenger RNA and protein, respectively. Cell proliferation was evaluated by the 5-bromo-2′-deoxyuridine DNA labeling assay. NF-κB phosphorylation was assayed by western blot. 1 × 106 of A549 or A549 sPLA2 knockdown cells were injected into the left flanks of nude mice (aged 6 to 8 weeks). Tumors were followed for 23 days, then removed and stained with hematoxylin and eosin, stained with Ki-67, and analyzed for sPLA2 IIa messenger RNA expression. Results sPLA2 knockdown reduced NF-κB phosphorylation and tumor growth in vivo. A549 wild-type tumors grew twice as fast as knockdown tumors. Ki-67 staining was more prominent throughout the wild-type tumors compared with knockdown tumors. Explanted knockdown tumors maintained lower sPLA2 levels compared with wild-type, confirmed by reverse transcriptase-polymerase chain reaction. Conclusions Knockdown of sPLA2 IIa suppresses lung cancer growth in part by attenuating NF-κB activity. These findings justify further investigation into the cellular mechanisms of sPLA2 in lung cancer and its potential role as a therapeutic target.

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confidence: 99%

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confidence: 99%

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Knockdown of secretory phospholipase A2 IIa reduces lung cancer growth in vitro and in vivo

Mauchley

et al. 2012

The Journal of Thoracic and Cardiovascular Surgery

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“…As cytosolic and secretory phospholipase A2 in mammalian cells is known to be related to the expression of ICAM1 (Thommesen et al, 1998; Zhu et al, 1999; Barnett et al, 2001; Yu et al, 2012), we examined whether SlaA induced the expression of adhesion molecules such as ICAM1 in HUVECs. SlaA upregulated the transcription of ICAM1 and VCAM1 mRNAs and the expression of ICAM1 and VCAM1 proteins, resulting in the adhesion of THP-1 cells.…”

Section: Discussionmentioning

confidence: 99%

Streptococcus pyogenes Phospholipase A2 Induces the Expression of Adhesion Molecules on Human Umbilical Vein Endothelial Cells and Aorta of Mice

Oda

Domon

Kurosawa

et al. 2017

Front. Cell. Infect. Microbiol.

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The Streptococcus pyogenes phospholipase A 2 (SlaA) gene is highly conserved in the M3 serotype of group A S. pyogenes, which often involves hypervirulent clones. However, the role of SlaA in S. pyogenes pathogenesis is unclear. Herein, we report that SlaA induces the expression of intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1) via the arachidonic acid signaling cascade. Notably, recombinant SlaA induced ICAM1 and VCAM1 expression in human umbilical vein endothelial cells (HUVECs), resulting in enhanced adhesion of human monocytic leukemia (THP-1) cells. However, C134A, a variant enzyme with no enzymatic activity, did not induce such events. In addition, culture supernatants from S. pyogenes SSI-1 enhanced the adhesion of THP-1 cells to HUVECs, but culture supernatants from the slaA isogenic mutant strain had limited effects. Aspirin, a cyclooxygenase 2 inhibitor, prevented the adhesion of THP-1 cells to HUVECs and did not induce ICAM1 and VCAM1 expression in HUVECs treated with SlaA. However, zileuton, a 5-lipoxygenase inhibitor, did not exhibit such effects. Furthermore, pre-administration of aspirin in mice intravenously injected with SlaA attenuated the transcriptional abundance of ICAM1 and VCAM1 in the aorta. These results suggested that SlaA from S. pyogenes stimulates the expression of adhesion molecules in vascular endothelial cells. Thus, SlaA contributes to the inflammation of vascular endothelial cells upon S. pyogenes infection.

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“…It has been implicated as a factor in the progression of prostate, esophageal, colon, and lung cancer [4–10]. Furthermore, we have shown that this enzyme contributes to tumor growth in vivo and invasion in vitro, specifically in human lung cancer cells [8, 9]. …”

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Cancer Stem Cell Phenotype Is Supported by Secretory Phospholipase A2 in Human Lung Cancer Cells

Bennett

Deng

et al. 2014

The Annals of Thoracic Surgery

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Background Lung cancer stem cells (CSCs) are a sub-population of cells that drive growth, invasiveness, and resistance to therapy. Inflammatory eicosanoids are critical to maintain this malignant subpopulation. Secretory phospholipase A2 group IIa (sPLA2) is an important mediator of the growth and invasive potential of human lung cancer cells and regulates eicosanoid production. We hypothesized that sPLA2 plays a role in the maintenance of lung CSCs. Methods Cancer stem cells from lung adenocarcinoma cell lines H125 and A549 were isolated using aldehyde dehydrogenase activity and flow cytometry. Protein and mRNA levels for sPLA2 were compared between sorted cells using Western blotting and quantitative reverse transcriptase–polymerase chain reaction techniques. Chemical inhibition of sPLA2 and short-hairpin RNA knockdown of sPLA2 were used to evaluate effects on tumorsphere formation. Results Lung CSCs were isolated in 8.9% ± 4.1% (mean ± SD) and 4.1% ± 1.6% of H125 and A549 cells respectively. Both sPLA2 protein and mRNA expression were significantly elevated in the CSC subpopulation of H125 (p = 0.002) and A549 (p = 0.005; n = 4). Knockdown of sPLA2 significantly reduced tumorsphere formation in H125 (p = 0.026) and A549 (p = 0.001; n = 3). Chemical inhibition of sPLA2 resulted in dose-dependent reduction in tumorsphere formation in H125 (p = 0.003) and A549 (p = 0.076; n = 3). Conclusions Lung CSCs express higher levels of sPLA2 than the non–stem cell population. Our findings that viral knockdown and chemical inhibition of sPLA2 reduce tumorsphere formation in lung cancer cells demonstrate for the first time that sPLA2 plays an important role in CSCs. These findings suggest that sPLA2 may be an important therapeutic target for human lung cancer.

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Lung cancer cell invasion and expression of intercellular adhesion molecule-1 (ICAM-1) are attenuated by secretory phospholipase A2 inhibition

Cited by 39 publications

References 20 publications

Knockdown of secretory phospholipase A2 IIa reduces lung cancer growth in vitro and in vivo

Knockdown of secretory phospholipase A2 IIa reduces lung cancer growth in vitro and in vivo

Streptococcus pyogenes Phospholipase A2 Induces the Expression of Adhesion Molecules on Human Umbilical Vein Endothelial Cells and Aorta of Mice

Cancer Stem Cell Phenotype Is Supported by Secretory Phospholipase A2 in Human Lung Cancer Cells

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