The ‌BCL2-associated athanogene-3–Interferon-induced transmembrane protein 2 axis enhances pancreatic ductal adenocarcinoma growth via the Mitogen-activated protein kinase signaling pathway

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy, exhibits escalating incidence and mortality rates, underscoring the urgent need for the identification of novel therapeutic targets and strategies. The BCL2-associated athanogene-3 (BAG3) protein, a multifunctional regulator involved in various cellular processes, notably plays a crucial role in promoting tumor progression and acts as a potential “bridge” between tumors and the tumor microenvironment. In this study, we demonstrate that PDAC cells secrete BAG3 (sBAG3), which engages the interferon-induced transmembrane protein 2 (IFITM2) receptor to activate the mitogen-activated protein kinase signaling pathway, specifically enhancing phospho-extracellular regulated protein (pERK) activity, thereby propelling PDAC growth. Furthermore, our preliminary investigation into the effects of sBAG3 on co-cultured natural killer cells intriguingly discovered that sBAG3 diminishes natural killer cell cytotoxicity and active molecule expression. In conclusion, our findings confirm the pivotal role of the sBAG3–IFITM2 axis in fostering PDAC progression, highlighting the potential significance of sBAG3 as a dual therapeutic target for both tumor and immune cells.