Phosphoinositide and redox dysregulation by the anticancer methylthioadenosine phosphorylase transition state inhibitor |
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| Affiliation: | 1. School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand;2. Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Australia;3. School of Chemistry, University of Melbourne, Parkville, Australia;4. Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA;5. Ferrier Research Institute, Victoria University of Wellington, Wellington, New Zealand;6. Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, Parkville, Australia;1. State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, 830017, China;2. State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Functional Center, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, 830017, China;3. Department of Laparoscopic Surgery, First Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang 830002, China;4. Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China;5. Pathology Center, Xinjiang Medical University Affiliated Tumor Hospital, Urumqi, Xinjiang 830002, China;1. Servicio de Bioquímica Clínica, UCA-CCM, HU Ramón y Cajal-IRYCIS, Madrid, Spain;2. Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), Murcia, Spain;3. Servicio de Bioquímica-Investigación, HU Ramón y Cajal-IRYCIS, Madrid, Spain;4. Servicio de Gastroenterología, HU Ramón y Cajal-IRYCIS, Madrid, Spain;5. Servicio de Cirugía General, HCU Virgen de la Victoria, Málaga, Spain;6. Servicio de Anatomía Patológica, HU Ramón y Cajal-IRYCIS, Madrid, Spain;7. Departamento de Cirugía General y Aparato Digestivo, HU Virgen de la Arraixaca, Murcia, Spain;8. CIBER de Enfermedades Hepáticas y Digestivas (CIBEREHD), ISCIII, Spain;1. Department of Medical Biotechnology and Translational Medicine, University of Milano, 20054 Segrate, Milano, Italy;2. UK Dementia Research Institute at UCL, London, UK;3. Neuro-Sys, 410 Chemin Départemental 60, 13120 Gardanne, France;4. Department of Immunology, St. Jude Children''s Research Hospital, Memphis, TN 38105, USA;5. Department of Chemistry, University of Milano, Milan, Italy |
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| Abstract: | Methylthio-DADMe-immucillin-A (MTDIA) is an 86 picomolar inhibitor of 5′-methylthioadenosine phosphorylase (MTAP) with potent and specific anti-cancer efficacy. MTAP salvages S-adenosylmethionine (SAM) from 5′-methylthioadenosine (MTA), a toxic metabolite produced during polyamine biosynthesis. Changes in MTAP expression are implicated in cancer growth and development, making MTAP an appealing target for anti-cancer therapeutics. Since SAM is involved in lipid metabolism, we hypothesised that MTDIA alters the lipidomes of MTDIA-treated cells. To identify these effects, we analysed the lipid profiles of MTDIA-treated Saccharomyces cerevisiae using ultra-high resolution accurate mass spectrometry (UHRAMS). MTAP inhibition by MTDIA, and knockout of the Meu1 gene that encodes for MTAP in yeast, caused global lipidomic changes and differential abundance of lipids involved in cell signaling. The phosphoinositide kinase/phosphatase signaling network was specifically impaired upon MTDIA treatment, and was independently validated and further characterised via altered localization of proteins integral to this network. Functional consequences of dysregulated lipid metabolism included a decrease in reactive oxygen species (ROS) levels induced by MTDIA that was contemporaneous with changes in immunological response factors (nitric oxide, tumour necrosis factor-alpha and interleukin-10) in mammalian cells. These results indicate that lipid homeostasis alterations and concomitant downstream effects may be associated with MTDIA mechanistic efficacy. |
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