CDB25:0004099 PLA2G2A — ERBB3

ABSTRACT: 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 IIa (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-κB 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‑IIa 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 microenvironment 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.