title: Secretory phospholipase A2-IIa upregulates HER/HER2-elicited signaling in lung cancer cells.
abstract: Lung cancer is the leading cause of cancer death worldwide. There is an urgent need for early diagnostic tools and novel therapies in order to increase lung cancer survival. Secretory phospholipase A2 group IIa (sPLA2-IIa) is involved in inflammation, tumorigenesis and metastasis. We were the first to uncover that cancer cells secrete sPLA2‑IIa. sPLA2‑IIa is overexpressed in almost all specimens of human lung cancers examined and is significantly elevated in the plasma of lung cancer patients. High levels of plasma sPLA2-IIa are significantly associated with advanced stage and decreased overall cancer survival. In this study, we further showed that elevated HER/HER2‑PI3K-Akt-NF-κB signaling contributes to sPLA2-IIa overexpression in lung cancer cells. sPLA2-IIa in turn phosphorylates and activates HER2 and HER3 in a time- and dose‑dependent manner in lung cancer cells. The structure and sequence‑based docking analysis revealed that sPLA2-IIa β hairpin shares structural similarity with the corresponding EGF hairpin. sPLA2-IIa forms an extensive interface with EGFR and brings the two lobes of EGFR into an active conformation. sPLA2-IIa also enhances the NF-κB promoter activity. Anti-sPLA2-IIa antibody, but not the small molecule sPLA2-IIa inhibitor LY315920, significantly inhibits sPLA2‑IIa-induced activation of NF-κB promoter. Our findings support the notion that sPLA2-IIa functions as a ligand for the EGFR family of receptors leading to an elevated HER/HER2-elicited signaling. Plasma sPLA2-IIa can potentially serve as lung cancer biomarker and sPLA2‑IIa is a potential therapeutic target against lung cancer.
authors.affiliation: Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
authors.forename: Zhongyun
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Meller
authors.affiliation: Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Succop
authors.affiliation: Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Wikenheiser-Brokamp
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Starnes
authors.affiliation: Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Lu
mesh_terms: D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000097:blood; D002460:Cell Line; D015972:Gene Expression Regulation, Neoplastic; D054501:Group II Phospholipases A2 / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D062105:Molecular Docking Simulation; D020890:Neuregulin-1 / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D014408:Biomarkers, Tumor; D054501:Group II Phospholipases A2; D020890:Neuregulin-1; D017346:Protein Serine-Threonine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D000097782:NF-kappaB-Inducing Kinase; C094131:NRG1 protein, human; C508053:ERBB2 protein, human; C516287:PLA2G2A protein, human