The extracellular matrix component perlecan/HSPG2 regulates radioresistance in prostate cancer cells.
1. Front Cell Dev Biol. 2024 Aug 1;12:1452463. doi: 10.3389/fcell.2024.1452463. eCollection 2024. The extracellular matrix component perlecan/HSPG2 regulates radioresistance in prostate cancer cells. Samaržija I(1)(2), Lukiyanchuk V(3), Lončarić M(1), Rac-Justament A(1), Stojanović N(1), Gorodetska I(4), Kahya U(3)(4), Humphries JD(5), Fatima M(6), Humphries MJ(6), Fröbe A(7), Dubrovska A(3)(4)(8)(9)(10), Ambriović-Ristov A(1). Author information: (1)Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia. (2)Laboratory for Epigenomics, Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia. (3)Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, Dresden, Germany. (4)OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany. (5)Department of Life Sciences, Manchester Metropolitan University, Manchester, United Kingdom. (6)Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom. (7)Department of Oncology and Nuclear Medicine, Sestre Milosrdnice University Hospital Center, School of Dental Medicine, University of Zagreb, Zagreb, Croatia. (8)German Cancer Consortium, Partner Site Dresden and German Cancer Research Center, Heidelberg, Germany. (9)National Center for Tumor Diseases, Partner Site Dresden: German Cancer Research Center, Heidelberg, Germany. (10)Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany. Radiotherapy of prostate cancer (PC) can lead to the acquisition of radioresistance through molecular mechanisms that involve, in part, cell adhesion-mediated signaling. To define these mechanisms, we employed a DU145 PC model to conduct a comparative mass spectrometry-based proteomic analysis of the purified integrin nexus, i.e., the cell-matrix junction where integrins bridge assembled extracellular matrix (matrisome components) to adhesion signaling complexes (adhesome components). When parental and radioresistant cells were compared, the expression of integrins was not changed, but cell radioresistance was associated with extensive matrix remodeling and changes in the complement of adhesion signaling proteins. Out of 72 proteins differentially expressed in the parental and radioresistant cells, four proteins were selected for functional validation based on their correlation with biochemical recurrence-free survival. Perlecan/heparan sulfate proteoglycan 2 (HSPG2) and lysyl-like oxidase-like 2 (LOXL2) were upregulated, while sushi repeat-containing protein X-linked (SRPX) and laminin subunit beta 3 (LAMB3) were downregulated in radioresistant DU145 cells. Knockdown of perlecan/HSPG2 sensitized radioresistant DU145 RR cells to irradiation while the sensitivity of DU145 parental cells did not change, indicating a potential role for perlecan/HSPG2 and its associated proteins in suppressing tumor radioresistance. Validation in androgen-sensitive parental and radioresistant LNCaP cells further supported perlecan/HSPG2 as a regulator of cell radiosensitivity. These findings extend our understanding of the interplay between extracellular matrix remodeling and PC radioresistance and signpost perlecan/HSPG2 as a potential therapeutic target and biomarker for PC. Copyright © 2024 Samaržija, Lukiyanchuk, Lončarić, Rac-Justament, Stojanović, Gorodetska, Kahya, Humphries, Fatima, Humphries, Fröbe, Dubrovska and Ambriović-Ristov. DOI: 10.3389/fcell.2024.1452463 PMCID: PMC11325029 PMID: 39149513 Conflict of interest statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
