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

• Published in: Carcinogenesis (New York) 2024-12, Vol.45 (12), p.928-939
• Main Authors: Wang, Peipei, Chen, Congliang, Lin, Kexin, Zhang, Yu, Hu, Junmei, Zhu, Tongbo, Wang, Xia
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic - drug effects; Humans; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; MAP Kinase Signaling System - drug effects; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Signal Transduction; Tumor Microenvironment
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/bgae053

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.