Saravanan Thiyagarajan

Publications (4)20.04 Total impact

• Source

  Available from: Phuoc T Tran

  Article: Nelfinavir induces radiation sensitization in pituitary adenoma cells.

  Jing Zeng, Alfred P See, Khaled Aziz, Saravanan Thiyagarajan, Tarek Salih, Rajendra P Gajula, Michael Armour, Jillian Phallen, Stephanie Terezakis, Lawrence Kleinberg, Kristen Redmond, Russell K Hales, Roberto Salvatori, Alfredo Quinones-Hinojosa, Phuoc T Tran, Michael Lim
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  ABSTRACT: Pituitary adenomas with local invasion and high secretory activity remain a therapeutic challenge. The HIV protease inhibitor nelfinavir is a radiosensitizer in multiple tumor models. We tested nelfinavir as a radiosensitizer in pituitary adenoma cells in vitro and in vivo. We examined the effect of nelfinavir with radiation on in vitro cell viability, clonogenic survival, apoptosis, prolactin secretion, cell cycle distribution, and the PI3K-AKT-mTOR pathway. We evaluated tumor growth delay and confirmed nelfinavir's effect on the PI3K-AKT-mTOR pathway in a hind-flank model. Nelfinavir sensitized pituitary adenoma cells to ionizing radiation as shown by viability assays and clonogenic assay with an enhancement ratio of 1.2 (p < 0.05). There is increased apoptotic cell death, as determined by annexin-V expression and cleaved caspase-3 levels. Nelfinavir does not affect prolactin secretion or cell cycle distribution. In vivo, untreated tumors reached 4-fold volume in 12 days, 17 days with nelfinavir treatment, 27 days with radiation 6 Gy, and 41 days with nelfinavir plus radiation (one-way ANOVA p < 0.001). Decreased phospho-S6 on Western blotting in vitro and immunohistochemistry in vivo demonstrated nelfinavir inhibition of the PI3K-AKT-mTOR pathway. Our data suggests a promising combination therapy with nelfinavir plus radiation in pituitary adenomas, which should be investigated in clinical studies.
  Cancer biology & therapy 10/2011; 12(7):657-63. · 2.64 Impact Factor
• Article: Role of GLI2 transcription factor in growth and tumorigenicity of prostate cells.

  Saravanan Thiyagarajan, Neehar Bhatia, Shannon Reagan-Shaw, Diana Cozma, Andrei Thomas-Tikhonenko, Nihal Ahmad, Vladimir S Spiegelman
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  ABSTRACT: Aberrant activation of the Hedgehog (Hh) signaling pathway has been reported in various cancer types including prostate cancer. The GLI2 transcription factor is a primary mediator of Hh signaling. However, its relative contribution to development of prostate tumors is poorly understood. To establish the role of GLI2 in maintaining the tumorigenic properties of prostate cancer cells, we developed GLI2-specific small hairpin RNA. Knockdown of GLI2 in these cells resulted in significant down-regulation of the Hh signaling pathway, followed by inhibition of colony formation, anchorage-independent growth, and growth of xenografts in vivo. Conversely, ectopic expression of Gli2 in nontumorigenic prostate epithelial cells resulted in accelerated cell cycle progression, especially transition through G(2)-M, and augmented proliferation. Altogether, our findings suggest that GLI2 plays a critical role in the malignant phenotype of prostate cancer cells, and GLI2 may potentially become an attractive therapeutic target for the treatment of prostate cancer.
  Cancer Research 12/2007; 67(22):10642-6. · 7.86 Impact Factor
• Article: Gli2 is targeted for ubiquitination and degradation by beta-TrCP ubiquitin ligase.

  Neehar Bhatia, Saravanan Thiyagarajan, Irina Elcheva, Mohammed Saleem, Andrzej Dlugosz, Hasan Mukhtar, Vladimir S Spiegelman
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  ABSTRACT: The Hedgehog (Hh) signaling pathway plays a crucial role in embryogenesis and has been linked to the development of several human malignancies. The transcription factor Gli2 plays a key role in the transduction of Hh signals by modulating transcription of some Hh target genes, yet the mechanisms that control Gli2 protein expression are largely unknown. Here we report that beta-transducin repeat-containing protein (beta-TrCP) E3 ubiquitin ligase is required for Gli2 degradation. beta-TrCP2 directly binds wild type Gli2 and promotes its ubiquitination. Single amino acid substitution in Gli2 putative binding site inhibits its interaction with beta-TrCP2, its ubiquitination, and stabilizes the Gli2 protein. Stable Gli2 mutant is expressed in higher levels and is more potent in the activation of Gli-dependent transcription as compared with wild type Gli2. We also found that GLI2 protein is expressed highly in prostate cancer cell lines and primary tumors, whereas the level of GLI2 mRNA is not appreciably different in normal and neoplastic prostate. These data identify beta-TrCP2 as a pivotal regulator of Gli2 expression and point to an important role for posttranslational modulation of GLI2 protein levels in Hh pathway-associated human prostate cancer.
  Journal of Biological Chemistry 08/2006; 281(28):19320-6. · 4.77 Impact Factor
• Article: Gli2 Is Targeted for Ubiquitination and Degradation by β-TrCP Ubiquitin Ligase

  Neehar Bhatia, Saravanan Thiyagarajan, Irina Elcheva, Mohammed Saleem, Andrzej Dlugosz, Hasan Mukhtar, Vladimir S. Spiegelman
  [show abstract] [hide abstract]
  ABSTRACT: The Hedgehog (Hh) signaling pathway plays a crucial role in embryogenesis and has been linked to the development of several human malignancies. The transcription factor Gli2 plays a key role in the transduction of Hh signals by modulating transcription of some Hh target genes, yet the mechanisms that control Gli2 protein expression are largely unknown. Here we report that β-transducin repeat-containing protein (β-TrCP) E3 ubiquitin ligase is required for Gli2 degradation. β-TrCP2 directly binds wild type Gli2 and promotes its ubiquitination. Single amino acid substitution in Gli2 putative binding site inhibits its interaction with β-TrCP2, its ubiquitination, and stabilizes the Gli2 protein. Stable Gli2 mutant is expressed in higher levels and is more potent in the activation of Gli-dependent transcription as compared with wild type Gli2. We also found that GLI2 protein is expressed highly in prostate cancer cell lines and primary tumors, whereas the level of GLI2 mRNA is not appreciably different in normal and neoplastic prostate. These data identify β-TrCP2 as a pivotal regulator of Gli2 expression and point to an important role for posttranslational modulation of GLI2 protein levels in Hh pathway-associated human prostate cancer.
  Journal of Biological Chemistry 07/2006; 281(28):19320-19326. · 4.77 Impact Factor