SRP19 and the protein secretion machinery is a targetable vulnerability in cancers with APC loss

Xi, X; Liu, L; Tuano, N; Tailhades, J; Mouradov, D; Steen, J; Sieber, O; Cryle, M; Nguyen-Dumont, T; Segelov, E; Rosenbluh, J

Author(s): Xi, X; Liu, L; Tuano, N; Tailhades, J; Mouradov, D; Steen, J; Sieber, O; Cryle, M; Nguyen-Dumont, T; Segelov, E; Rosenbluh, J;
Details: Publication Year 2025-04-15,Volume 122,Issue #15,Page e2409677122
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Abstract: Loss of the tumor suppressor gene (TSG) Adenomatous Polyposis Coli (APC) is a hallmark event in colorectal cancers. Since it is not possible to directly target a TSG, no treatment options are available for these patients. Here, we identify SRP19 and the protein secretion machinery as a unique vulnerability in cancers with heterozygous APC loss. SRP19 is located 15 kb from APC and is almost always codeleted in these tumors. Heterozygous APC/SRP19 loss leads to lower levels of SRP19 mRNA and protein. Consequently, cells with APC/SRP19 loss are vulnerable to partial suppression of SRP19. Moreover, we show that SRP19 is rate limiting for the formation of the Signal Recognition Particle, a complex that mediates ER-protein translocation, and thus, heterozygous SRP19 loss leads to less protein secretion and higher levels of ER-stress. As a result, low-dose arsenic trioxide induces ER-stress and inhibits proliferation in cultured cell lines and animal models. Our work identifies a strategy to treat cancers with APC deletion and provides a framework for identifying and translating vulnerabilities associated with loss of a TSG.
Keywords: Humans; Animals; *Adenomatous Polyposis Coli Protein/genetics/metabolism; Mice; *Signal Recognition Particle/metabolism/genetics; Endoplasmic Reticulum Stress/drug effects/genetics; Cell Line, Tumor; Cell Proliferation/drug effects; Protein Transport; *Adenomatous Polyposis Coli/genetics/metabolism; Genes, APC; APC loss; Srp19; arsenic trioxide; colon cancer; targeted therapy
Research Division(s): Personalised Oncology
Publisher's Version: https://doi.org/10.1073/pnas.2409677122
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-05-06 09:11:28

Last Modified: 2025-05-06 09:11:51