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.
Agostinelli, C., Carloni, S., Limarzi, F., Righi, S., Laginestra, M.A., Musuraca, G., et al. (2017). The emerging role of GSK-3β in the pathobiology of classical Hodgkin lymphoma. HISTOPATHOLOGY, 0, 0-0 [10.1111/his.13189].
The emerging role of GSK-3β in the pathobiology of classical Hodgkin lymphoma
AGOSTINELLI, CLAUDIO;LIMARZI, FRANCESCO;RIGHI, SIMONA;LAGINESTRA, MARIA ANTONELLA;MUSURACA, GERARDO;FIORENTINO, MICHELANGELO;NAPOLITANO, ROBERTA PIA;CUNEO, ANTONIO;ZINZANI, PIER LUIGI;SABATTINI, ELENA;PILERI, STEFANO;
2017
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.