Claudio Agostinelli1, Silvia Carloni2, Francesco Limarzi1, Simona Righi1, Maria Antonella Laginestra1, Gerardo Musuraca3, Michelangelo Fiorentino4, Roberta Napolitano2, Antonio Cuneo5, Daniele Vergara6, Pier Luigi Zinzani7, Elena Sabattini1, Stefano A Pileri8,9, Serena De Matteis2. 1. Hematopathology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology 'L. e A. Seragnoli', University of Bologna, Bologna, Italy. 2. Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola, Italy. 3. Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola, Italy. 4. Pathology Service, Addarii Institute of Oncology, S-Orsola-Malpighi Hospital, Bologna, Italy. 5. Department of Medical Sciences, University of Ferrara-Arcispedale Sant'Anna, Ferrara, Italy. 6. Laboratory of Clinical Proteomic, 'Giovanni Paolo II' Hospital, ASL-Lecce, Italy. 7. Hemathology Section, Department of Experimental, Diagnostic and Specialty Medicine, Bologna University School of Medicine, Bologna, Italy. 8. Professor Alma Mater Bologna University, Bologna, Italy. 9. Hematopathology Unit, European Institute of Oncology, Milan, Italy.
Abstract
AIMS: Glycogen synthase kinase-3 beta (GSK-3β) is a serine/threonine kinase involved in glycogen metabolism, cell cycle progression, differentiation, embryogenesis, migration, metabolism, survival and cellular senescence. Its main biological function is to inhibit β-catenin by sequestration and promotion of its proteasomal degradation in the Wnt canonical pathway; however, GSK-3β interacts with multiple signalling pathways, and aberrant expression of the enzyme was reported in many solid neoplasms. This study aimed to investigate the biological relevance of GSK-3β in classical Hodgkin lymphomas (cHL). METHODS AND RESULTS: We analysed the functional status of GSK-3β enzyme in cHL by using antibodies raised against fixation-resistant epitopes of phospho Y216 GSK-3β (active form), phospho S9 GSK-3β (inactive form) and β-catenin protein. We first detected the pY216 GSK-3β active form of the enzyme in 100 of 100 (100%) of the cases, and in line with the latter expression profile, the β-catenin protein was found in only 12 of 100 (12%) of the samples. As reported previously in bladder cancer, pancreatic adenocarcinoma and chronic lymphocytic leukaemia, we showed an aberrant nuclear localization in the neoplastic clone of active pY216 GSK-3β in 78 of 100 (78%) of cHL cases. CONCLUSIONS: We demonstrated the activation of GSK-3β in cHL resulting in inhibition of the Wnt/β-catenin signal cascade and the aberrant accumulation of its activated form in nuclei of Hodgkin Reed-Sternberg and Hodgkin cells. These findings may be relevant for future clinical studies, identifying GSK-3β as a potential therapeutic target for cHL.
AIMS: Glycogen synthase kinase-3 beta (GSK-3β) is a serine/threonine kinase involved in glycogen metabolism, cell cycle progression, differentiation, embryogenesis, migration, metabolism, survival and cellular senescence. Its main biological function is to inhibit β-catenin by sequestration and promotion of its proteasomal degradation in the Wnt canonical pathway; however, GSK-3β interacts with multiple signalling pathways, and aberrant expression of the enzyme was reported in many solid neoplasms. This study aimed to investigate the biological relevance of GSK-3β in classical Hodgkin lymphomas (cHL). METHODS AND RESULTS: We analysed the functional status of GSK-3β enzyme in cHL by using antibodies raised against fixation-resistant epitopes of phospho Y216 GSK-3β (active form), phospho S9 GSK-3β (inactive form) and β-catenin protein. We first detected the pY216 GSK-3β active form of the enzyme in 100 of 100 (100%) of the cases, and in line with the latter expression profile, the β-catenin protein was found in only 12 of 100 (12%) of the samples. As reported previously in bladder cancer, pancreatic adenocarcinoma and chronic lymphocytic leukaemia, we showed an aberrant nuclear localization in the neoplastic clone of active pY216 GSK-3β in 78 of 100 (78%) of cHL cases. CONCLUSIONS: We demonstrated the activation of GSK-3β in cHL resulting in inhibition of the Wnt/β-catenin signal cascade and the aberrant accumulation of its activated form in nuclei of Hodgkin Reed-Sternberg and Hodgkin cells. These findings may be relevant for future clinical studies, identifying GSK-3β as a potential therapeutic target for cHL.
Authors: Serena De Matteis; Andrea Ragusa; Giorgia Marisi; Stefania De Domenico; Andrea Casadei Gardini; Massimiliano Bonafè; Anna Maria Giudetti Journal: Oxid Med Cell Longev Date: 2018-11-04 Impact factor: 6.543