INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer.

Autor: Rodgers SJ; Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia., Ooms LM; Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia., Oorschot VMJ; Monash Ramaciotti Centre for Cryo Electron Microscopy, a Node of Microscopy Australia, Monash University, Victoria, Australia.; Electron Microscopy Core Facility, European Molecular Biology Laboratory, Heidelberg, Germany., Schittenhelm RB; Monash Proteomics and Metabolomics Facility, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia., Nguyen EV; Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia., Hamila SA; Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia., Rynkiewicz N; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.; Babraham Institute, Cambridge, UK., Gurung R; Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia., Eramo MJ; Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia., Sriratana A; Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia., Fedele CG; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.; Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia., Caramia F; Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia., Loi S; Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia., Kerr G; Development and Stem Cells Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.; Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia., Abud HE; Development and Stem Cells Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.; Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia., Ramm G; Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.; Monash Ramaciotti Centre for Cryo Electron Microscopy, a Node of Microscopy Australia, Monash University, Victoria, Australia., Papa A; Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia., Ellisdon AM; Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC, Australia., Daly RJ; Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia., McLean CA; Department of Anatomical Pathology, Alfred Hospital, Prahran, VIC, Australia., Mitchell CA; Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia. christina.mitchell@monash.edu.; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia. christina.mitchell@monash.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 May 25; Vol. 12 (1), pp. 3140. Date of Electronic Publication: 2021 May 25.
DOI: 10.1038/s41467-021-23241-6
Abstrakt: INPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P 2 to PI(3)P and INPP4B inactivation is common in triple-negative breast cancer. Paradoxically, INPP4B is also a reported oncogene in other cancers. How these opposing INPP4B roles relate to PI3K regulation is unclear. We report PIK3CA-mutant ER + breast cancers exhibit increased INPP4B mRNA and protein expression and INPP4B increased the proliferation and tumor growth of PIK3CA-mutant ER + breast cancer cells, despite suppression of AKT signaling. We used integrated proteomics, transcriptomics and imaging to demonstrate INPP4B localized to late endosomes via interaction with Rab7, which increased endosomal PI3Kα-dependent PI(3,4)P 2 to PI(3)P conversion, late endosome/lysosome number and cargo trafficking, resulting in enhanced GSK3β lysosomal degradation and activation of Wnt/β-catenin signaling. Mechanistically, Wnt inhibition or depletion of the PI(3)P-effector, Hrs, reduced INPP4B-mediated cell proliferation and tumor growth. Therefore, INPP4B facilitates PI3Kα crosstalk with Wnt signaling in ER + breast cancer via PI(3,4)P 2 to PI(3)P conversion on late endosomes, suggesting these tumors may be targeted with combined PI3K and Wnt/β-catenin therapies.
Databáze: MEDLINE
Externí odkaz: