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.

Overexpression of secretory phospholipase A2-IIa supports cancer stem cell phenotype via HER/ERBB-elicited signaling in lung and prostate cancer cells

“…The most recent report by others supports our finding in that high levels of plasma sPLA2-IIa are associated with poor prognosis of cancers (31). More importantly, we revealed that elevated HER/ERBB-PI3K-Akt-NF-κB signaling induces sPLA2-IIa overexpression and secretion in both lung and prostate cancer cells; in turn, sPLA2-IIa stimulates its overexpression via HER/ERBB-elicited signaling in the positive feedback regulation manner (26,32). sPLA2-IIa induces phosphorylation of HER2 and HER3 in a dose-dependent manner in NSCSC A549 and H1975 cells (32).…”

“…Furthermore, sPLA2-IIa directly interacts with and activates EGFR family receptors, suggesting that sPLA2-IIa is a ligand for both EGFR and HER3. These findings, together with our previous data (13,29,30,32), support the notion that high levels of sPLA2-IIa in the tumor microenvironment support CSC phenotype via HER/ERBB-elicited signaling, and sPLA2-IIa is a novel therapeutic target against cancer and CSCs.…”

“…More importantly, we revealed that elevated HER/ERBB-PI3K-Akt-NF-κB signaling induces sPLA2-IIa overexpression and secretion in both lung and prostate cancer cells; in turn, sPLA2-IIa stimulates its overexpression via HER/ERBB-elicited signaling in the positive feedback regulation manner (26,32). sPLA2-IIa induces phosphorylation of HER2 and HER3 in a dose-dependent manner in NSCSC A549 and H1975 cells (32). However, the underlying molecular mechanisms of sPLA2-IIa at an aberrant high level in the tumor microenvironment in stimulating cancer progression and metastasis remains to be elucidated.…”

Epigenetics and miRNA as predictive markers and targets for lung cancer chemotherapy

“…1 Histologically, lung cancer is grouped into Non-small (NSCLC) and small-cell lung cancer (SCLC). Platinum-based therapy is commonly used for NSCLC in combination with a tubulin-binding agent, a camptothecin analog, gemcitabine, or pemetrexed.…”

Nucleolin internalizesBothrops asperLys49 phospholipase A2forming cell surface amyloid-like assemblies

“…However transmembrane proteins also can be involved, and they may not have been detected in our pull-down because they are more difficult to isolate and identify by mass spectrometry. In this regard it is worth remembering that both NCL and PLA2g2a interact with integrins and EGFR (47)(48)(49)(50). Since NCL is not a membrane protein, it will have to interact with transmembrane proteins to communicate with the cell interior and trigger the internalization process.…”