Abstract 4307: RAGE is the key receptor for LPA in lung and mammary cancer progression and metastasis

Abstract

Abstract Lung and breast cancer signaling are very complex; receptor for advanced glycation end products (RAGE) is highly expressed in various cancers and is correlated with poorer outcome in lung and other cancers. It is an immunoglobulin like membrane receptor shows binding with various ligands sharing structural likeness such as amyloid beta, advanced glycation end products (AGEs), S100B proteins, amphoterin and HMGB1 and mediates numerous inflammatory and cellular events including diseases including various cancers. LPA a RAGE ligand is a biologically active phospholipid involved in cell proliferation, migration and survival via its different G protein couple receptors (GPCRs). LPA and its signalling pathways have been implicated in different pathological conditions of lung tissue, including inflammation, fibrosis and cancer activating various signalling pathways. Here, we have identified RAGE-LPA signaling mechanisms showing AKT, STAT3 and ERK as downstream signaling pathways gets activated upon LPA treatment via RAGE receptor in both lung and breast cancer cells. RAGE knockdown with multiple independent shRNAs in lung and breast cancer cells led to decreased transwell invasion and soft agar colony formation, and proliferation upon LPA stimulation. Our RAGE silencing study in lung and breast cancer cells upon LPA treatment showed upregulation of specific oncogenes Cyclin D1, c-Myc and VEGF via RAGE receptor. RAGE association with LPA induced epithelial to mesenchymal transition (EMT) in both lung and breast cancer cells have also been observed by the RAGE attenuation studies by examining the expression of some EMT markers. The physiological significance of LPA-RAGE axis was exposed by our xenograft study by nude mice intraperitoneal injections of control and RAGE inhibited lung and mammary tumors generated by LPA doses in alternative days, results the formation of tumor foci on peritoneum wall via RAGE receptor. This study provides novel therapeutic insights as the use of RAGE blocking antibodies and antagonists or competitive inhibitors of LPA against RAGE might be useful of breast cancer treatment. This study also suggests that RAGE and LPA can be used as biomarkers for the early detection of lung and breast cancers. Citation Format: Nitish Jangde, Rashmi Ray, Vivek Rai. RAGE is the key receptor for LPA in lung and mammary cancer progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4307.