title: OGDHL is a modifier of AKT-dependent signaling and NF-κB function.
abstract: Oxoglutarate dehydrogenase (OGDH) is the first and rate-limiting component of the multi-enzyme OGDH complex (OGDHC) whose malfunction is associated with neuro-degeneration. The essential role of this complex is in the degradation of glucose and glutamate and the OGDHL gene (one component of OGDHC) is down-regulated by promoter hypermethylation in many different cancer types. These properties suggest a potential growth modulating role of OGDHL in cancer; however, the molecular mechanism through which OGDHL exerts its growth modulating function has not been elucidated.Here, we report that restoration of OGDHL expression in cervical cancer cells lacking endogenous OGDHL expression suppressed cell proliferation, invasion and soft agar colony formation in vitro. Knockdown of OGDHL expression in cervical cancer cells expressing endogenous OGDHL had the opposite effect. Forced expression of OGDHL increased the production of reactive oxygen species (ROS) leading to apoptosis through caspase 3 mediated down-regulation of the AKT signaling cascade and decreased NF-κB phosphorylation. Conversely, silencing OGDHL stimulated the signaling pathway via increased AKT phosphorylation. Moreover, the addition of caspase 3 or ROS inhibitors in the presence of OGDHL increased AKT signaling and cervical cancer cell proliferation.Taken together, these data suggest that inactivation of OGDHL can contribute to cervical tumorigenesis via activation of the AKT signaling pathway and thus support it as an important anti-proliferative gene in cervical cancer.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Tanusree
authors.initials: T
authors.lastname: Sen
authors.forename: Nilkantha
authors.initials: N
authors.lastname: Sen
authors.forename: Maartje G
authors.initials: MG
authors.lastname: Noordhuis
authors.forename: Rajani
authors.initials: R
authors.lastname: Ravi
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
authors.forename: Patrick K
authors.initials: PK
authors.lastname: Ha
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.forename: Mohammad Obaidul
authors.initials: MO
authors.lastname: Hoque
mesh_terms: D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007655:Ketoglutarate Dehydrogenase Complex / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D017382:Reactive Oxygen Species; D007655:Ketoglutarate Dehydrogenase Complex; D051057:Proto-Oncogene Proteins c-akt