Vincenzo N Talesa1, Ivana Ferri2, Guido Bellezza2, Harold D Love3, Angelo Sidoni2, Cinzia Antognelli1. 1. Division of Biosciences and Medical Embryology, Department of Experimental Medicine, School of Medicine and Surgery, University of Perugia, Perugia, Italy. 2. Division of Anatomic Pathology and Histology, Department of Experimental Medicine, School of Medicine and Surgery, University of Perugia, Perugia, Italy. 3. Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
Abstract
BACKGROUND: Glyoxalase 2 (Glo2), together with glyoxalase 1 (Glo1), forms the main scavenging system of methylglyoxal, a potent pro-apoptotic agent mainly generated by glycolysis. An increased rate of glycolysis is a well known signature of cancer cells. As a survival strategy, Glo1 is overexpressed in many human malignant cells, including prostate cancer (PCa), where it plays a crucial role in progression. No information is available on the role of Glo2 in the same ambit. PCa is the most common malignancy affecting men in the western world. Progression to a lethal hormone-refractory PCa represents the major concern in this pathology. Therefore, a deeper understanding of the molecular mechanisms underlying PCa invasiveness and metastasis is urgently needed in order to develop novel therapeutic targets for this incurable state of the malignancy. METHODS: Glo2 and Glo1 expression was examined in clinical samples of PCa by immunohistochemistry and in different PCa cell models by western blotting and quantitative real-time polymerase chain reaction. Gene silencing/overexpression and scavenging/inhibitory agents were used for functional analyses. RESULTS: We demonstrated that Glo2, together with Glo1, represents a novel mechanism in PCa progression as part of a pathway driven by PTEN/PI3K/AKT/mTOR signaling with involvement of PKM2 and ERα. Importantly, Glo1/Glo2 silencing did not alter the behavior of benign cells. CONCLUSIONS: Targeting glyoxalases metabolic pathway may represent a strategy to selectively inhibit advanced PCa. Prostate 77:196-210, 2017.
BACKGROUND:Glyoxalase 2 (Glo2), together with glyoxalase 1 (Glo1), forms the main scavenging system of methylglyoxal, a potent pro-apoptotic agent mainly generated by glycolysis. An increased rate of glycolysis is a well known signature of cancer cells. As a survival strategy, Glo1 is overexpressed in many human malignant cells, including prostate cancer (PCa), where it plays a crucial role in progression. No information is available on the role of Glo2 in the same ambit. PCa is the most common malignancy affecting men in the western world. Progression to a lethal hormone-refractory PCa represents the major concern in this pathology. Therefore, a deeper understanding of the molecular mechanisms underlying PCa invasiveness and metastasis is urgently needed in order to develop novel therapeutic targets for this incurable state of the malignancy. METHODS:Glo2 and Glo1 expression was examined in clinical samples of PCa by immunohistochemistry and in different PCa cell models by western blotting and quantitative real-time polymerase chain reaction. Gene silencing/overexpression and scavenging/inhibitory agents were used for functional analyses. RESULTS: We demonstrated that Glo2, together with Glo1, represents a novel mechanism in PCa progression as part of a pathway driven by PTEN/PI3K/AKT/mTOR signaling with involvement of PKM2 and ERα. Importantly, Glo1/Glo2 silencing did not alter the behavior of benign cells. CONCLUSIONS: Targeting glyoxalases metabolic pathway may represent a strategy to selectively inhibit advanced PCa. Prostate 77:196-210, 2017.
Authors: Rahul Jandial; Josh Neman; Punnajit P Lim; Daniel Tamae; Claudia M Kowolik; Gerald E Wuenschell; Sarah C Shuck; Alexandra K Ciminera; Luis R De Jesus; Ching Ouyang; Mike Y Chen; John Termini Journal: Int J Mol Sci Date: 2018-01-30 Impact factor: 5.923