title: Secretory phospholipase A2-IIa is involved in prostate cancer progression and may potentially serve as a biomarker for prostate cancer.
abstract: The majority of prostate cancers are indolent, whereas a significant portion of patients will require systemic treatment during the course of their disease. To date, only high Gleason scores are best associated with a poor prognosis in prostate cancer. No validated serum biomarker has been identified with prognostic power. Previous studies showed that secretory phospholipase A2-IIa (sPLA2-IIa) is overexpressed in almost all human prostate cancer specimens and its elevated levels are correlated with high tumor grade. Here, we found that sPLA2-IIa is overexpressed in androgen-independent prostate cancer LNCaP-AI cells relative to their androgen-dependent LNCaP cell counterparts. LNCaP-AI cells also secrete significantly higher levels of sPLA2-IIa. Blocking sPLA2-IIa function compromises androgen-independent cell growth. Inhibition of the ligand-induced signaling output of the HER network, by blocking PI3K-Akt signaling and the nuclear factor-kappaB (NF-κB)-mediated pathway, compromises both sPLA2-IIa protein expression and secretion, as a result of downregulation of sPLA2-IIa promoter activity. More importantly, we demonstrated elevated serum sPLA2-IIa levels in prostate cancer patients. High serum sPLA2-IIa levels are associated significantly with high Gleason score and advanced disease stage. Increased sPLA2-IIa expression was confirmed in prostate cancer cells, but not in normal epithelium and stroma by immunohistochemistry analysis. We showed that elevated signaling of the HER/HER2-PI3K-Akt-NF-κB pathway contributes to sPLA2-IIa overexpression and secretion by prostate cancer cells. Given that sPLA2-IIa overexpression is associated with prostate development and progression, serum sPLA2-IIa may serve as a prognostic biomarker for prostate cancer and a potential surrogate prostate biomarker indicative of tumor burden.
authors.affiliation: Department of Medicine, University of Cincinnati College of Medicine, 2120 East Galbraith Road, Cincinnati, OH 45237-0507, USA.
authors.forename: Zhongyun
authors.initials: Z
authors.lastname: Dong
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
authors.forename: Kieran F
authors.initials: KF
authors.lastname: Scott
authors.forename: Linda
authors.initials: L
authors.lastname: Levin
authors.forename: Krishnanath
authors.initials: K
authors.lastname: Gaitonde
authors.forename: R Bruce
authors.initials: RB
authors.lastname: Bracken
authors.forename: Barbara
authors.initials: B
authors.lastname: Burke
authors.forename: Qihui Jim
authors.initials: QJ
authors.lastname: Zhai
authors.forename: Jiang
authors.initials: J
authors.lastname: Wang
authors.forename: Leslie
authors.initials: L
authors.lastname: Oleksowicz
authors.forename: Shan
authors.initials: S
authors.lastname: Lu
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood*; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D054501:Group II Phospholipases A2 / Q000502:physiology*; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009367:Neoplasm Staging; D009376:Neoplasms, Hormone-Dependent / Q000097:blood / Q000235:genetics / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; D054501:Group II Phospholipases A2; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human