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.

Vav3 oncogene is involved in regulation of secretory phospholipase A2-IIa expression in prostate cancer

“…plasmid splA2-IIa(-800)-luc was generated by insertion of the pcr promoter fragment into pgl5-luc vector, which has been described previously (18). Anti-Vav3 antibodies were obtained from upstate Biotechnology (charlottesville, VA).…”

“…3A) (7,18). the Her/Her2-pI3K-Akt-nF-κB pathway contributes to splA2-IIa overexpression and secretion in prostate cancer cells (18). given that Vav3 is a signaling molecule in the Her/Her2-elicited pathway, we determined whether Vav3 regulates splA2-IIa expression and whether egFr inhibitors erlotinib and gefitinib, egFr and Her2 dual inhibitors lapatinib and cI-1033, and nF-κB inhibitor bortezomib could suppress basal and Vav3-mediated expression of the splA2-IIa gene.…”

“…elevated splA2-IIa expression is associated with androgen-independence and a more aggressive cancer phenotype in the spontaneous trAMp prostate cancer model (16). splA2-IIa is a nF-κB target gene (17,18). We recently showed that splA2-IIa is overexpressed in androgen-independent prostate cancer lncap-AI cells relative to their parental androgen-dependent cell line lncap, which may contribute to androgen-independent growth (18).…”

“…splA2-IIa is a nF-κB target gene (17,18). We recently showed that splA2-IIa is overexpressed in androgen-independent prostate cancer lncap-AI cells relative to their parental androgen-dependent cell line lncap, which may contribute to androgen-independent growth (18). elevated signaling of the Her/Her2-pI3K-Akt-nF-κB pathway contributes to splA2-IIa overexpression and secretion in prostate cancer cells (18).…”

“…We recently showed that splA2-IIa is overexpressed in androgen-independent prostate cancer lncap-AI cells relative to their parental androgen-dependent cell line lncap, which may contribute to androgen-independent growth (18). elevated signaling of the Her/Her2-pI3K-Akt-nF-κB pathway contributes to splA2-IIa overexpression and secretion in prostate cancer cells (18). We are the first to show that there is an elevated level of serum splA2-IIa in prostate cancer patients and serum splA2-IIa is a potential biomarker for prostate cancer.…”