OGDHL Is a Modifier of AKT-Dependent Signaling and NF-κB Function

Tanusree Sen, Nilkantha Sen, Maartje G. Noordhuis, Rajani Ravi, T. C. Wu, Patrick K. Ha, David Sidransky, Mohammad Obaidul Hoque

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere48770
JournalPloS one
Volume7
Issue number11
DOIs
StatePublished - Nov 12 2012

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uterine cervical neoplasms
modifiers (genes)
Uterine Cervical Neoplasms
Ketoglutarate Dehydrogenase Complex
Phosphorylation
Cell proliferation
caspase-3
Caspase 3
reactive oxygen species
Reactive Oxygen Species
cell proliferation
phosphorylation
Genes
Cells
Cell Proliferation
Gene Components
neoplasms
Growth
glutamates
carcinogenesis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Sen, T., Sen, N., Noordhuis, M. G., Ravi, R., Wu, T. C., Ha, P. K., ... Hoque, M. O. (2012). OGDHL Is a Modifier of AKT-Dependent Signaling and NF-κB Function. PloS one, 7(11), [e48770]. https://doi.org/10.1371/journal.pone.0048770

OGDHL Is a Modifier of AKT-Dependent Signaling and NF-κB Function. / Sen, Tanusree; Sen, Nilkantha; Noordhuis, Maartje G.; Ravi, Rajani; Wu, T. C.; Ha, Patrick K.; Sidransky, David; Hoque, Mohammad Obaidul.

In: PloS one, Vol. 7, No. 11, e48770, 12.11.2012.

Research output: Contribution to journalArticle

Sen, T, Sen, N, Noordhuis, MG, Ravi, R, Wu, TC, Ha, PK, Sidransky, D & Hoque, MO 2012, 'OGDHL Is a Modifier of AKT-Dependent Signaling and NF-κB Function', PloS one, vol. 7, no. 11, e48770. https://doi.org/10.1371/journal.pone.0048770
Sen T, Sen N, Noordhuis MG, Ravi R, Wu TC, Ha PK et al. OGDHL Is a Modifier of AKT-Dependent Signaling and NF-κB Function. PloS one. 2012 Nov 12;7(11). e48770. https://doi.org/10.1371/journal.pone.0048770
Sen, Tanusree ; Sen, Nilkantha ; Noordhuis, Maartje G. ; Ravi, Rajani ; Wu, T. C. ; Ha, Patrick K. ; Sidransky, David ; Hoque, Mohammad Obaidul. / OGDHL Is a Modifier of AKT-Dependent Signaling and NF-κB Function. In: PloS one. 2012 ; Vol. 7, No. 11.
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