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

Resistance to conventional chemotherapies remains a significant clinical challenge in treatment of cancer. The cancer stem cells (CSCs) have properties necessary for tumor initiation, resistance to therapy, and progression. HER/ERBB-elicited signaling supports CSC properties. Our previous studies revealed that secretory phospholipase A2 group Ha (sPLA2-IIa) is overexpressed in both prostate and lung cancer cells, leading to an aberrant high level in the interstitial fluid, i.e., tumor microenvironment and blood. HER/ERBB-PI3K-Akt-NF-kappa B signaling stimulates sPLA2-IIa overexpression, and in turn, sPLA2-IIa activates EGFR family receptors and HER/ERBB-elicited signaling and stimulates sPLA2-IIa overexpression in a positive feedback manner. The present study determined the molecular mechanisms of sPLA2-lla in stimulating HER/ERBB-elicited signaling and supporting CSC properties. We found that sPLA2-IIa binds both EGFR and HER3 demonstrated by co-immunoprecipitation experiments and also indirectly interacts with HER2, suggesting that sPLA2-IIa functions as a ligand for both EGFR and HER3. Furthermore, both side population CSCs from non-small cell lung cancer (NSCLC) A549 and H1975 cells and ALDH1-high CSCs from castration-resistant prostate cancer (CRPC) 22Rv1 cells overexpress sPLA2-IIa and produce tumors when inoculated into subcutis of nude mice. Given an aberrant high level of sPLA2-IIa in the tumor micro environment that should be much higher than that in the blood, our findings support the notion that sPLA2-IIa functions as a ligand for EGFR family receptors and supports CSC properties via HER/ERBB-elicited signaling, which may contribute to resistance to therapy and cancer progression.