Malignant brain tumors represent one of the most refractory cancers to therapy and remain incurable. Gliomas represent the most common type of brain tumors that occur in various grades, with the patient's prognosis inversely proportional to the grade. The long-term objective of my laboratory is to understand the cellular and molecular mechanisms that underlie tumor invasiveness in human gliomas. My laboratory has been active in the study of proteases and the biology of brain tumors, and data generated so far have indicated that changes in proteases are correlated with the changes in the grade of the tumors. The hypotheses are: 1) Regulation of MMP-9 in combination with cathepsin B or uPAR in xenograft cells via a plasmid construct expressing a siRNA message for either MMP-9 and uPAR (pMU) or MMP-9 and cathepsin B (pMC) will inhibit tumor growth and invasion; and 2) Regulation of these molecules using bicistronic RNAi constructs in xenograft cell lines will decrease/increase several signaling pathway molecules involved in cell survival, adhesion, migration and proliferation.
The Specific Aims to address these hypotheses are as follows:
Specific Aim 1. Evaluate the effect of vectors expressing siRNA targeting MMP-9, uPAR and cathepsin B, or a combination of these, on glioma cell growth and invasion both in vitro and in vivo. 1a. Determine the effect of vectors expressing bicistronic siRNA against MMP-9 and uPAR (pMU) or MMP-9 and cathepsin B (pMC) on MMP-9, uPAR and cathepsin B levels in glioma xenograft cell lines. 1b. Investigate and compare the effect of pMU or pMC on the invasive behavior of human glioma xenograft cells in in vitro models with that of control/mock, EV (empty vector) and SV (scrambled vector). 1c. Determine the effect of pMU or pMC on pre-established intracranial tumor growth or invasiveness of two glioma xenograft cells (XG3, and XG4) in nude mice.
Specific Aim 2. Determine the effect of pMU/pMC on the molecular mechanisms of proliferation, migration and apoptosis in glioma xenograft cell lines. 2a. Determine the effect of pMU and pMC constructs on adhesion and migration of glioma xenograft cell lines. 2b. Evaluate the effect of pMU/pMC on the molecular mechanism of proliferation in glioma xenograft cells. 2c. Evaluate the effect of pMU/pMC on the molecular mechanism of apoptosis. We anticipate that these results will substantially augment our understanding of how MMP-9, cathepsin B, and uPAR molecules are regulated; thus, information gained should be of help in developing new therapeutic approaches to treat glioblastomas. ? ? ? ?
|Zhuang, Thompson; Chelluboina, Bharath; Ponnala, Shivani et al. (2013) Involvement of nitric oxide synthase in matrix metalloproteinase-9- and/or urokinase plasminogen activator receptor-mediated glioma cell migration. BMC Cancer 13:590|
|Veeravalli, Krishna Kumar; Rao, Jasti S (2012) MMP-9 and uPAR regulated glioma cell migration. Cell Adh Migr 6:509-12|
|Veeravalli, Krishna Kumar; Ponnala, Shivani; Chetty, Chandramu et al. (2012) Integrin ?9?1-mediated cell migration in glioblastoma via SSAT and Kir4.2 potassium channel pathway. Cell Signal 24:272-81|
|Ponnala, Shivani; Chetty, Chandramu; Veeravalli, Krishna Kumar et al. (2012) Metabolic remodeling precedes mitochondrial outer membrane permeabilization in human glioma xenograft cells. Int J Oncol 40:509-18|
|Asuthkar, Swapna; Velpula, Kiran Kumar; Chetty, Chandramu et al. (2012) Epigenetic regulation of miRNA-211 by MMP-9 governs glioma cell apoptosis, chemosensitivity and radiosensitivity. Oncotarget 3:1439-54|
|Chetty, Chandramu; Vanamala, Sravan K; Gondi, Christopher S et al. (2012) MMP-9 induces CD44 cleavage and CD44 mediated cell migration in glioblastoma xenograft cells. Cell Signal 24:549-59|
|Ponnala, Shivani; Chetty, Chandramu; Veeravalli, Krishna Kumar et al. (2011) MMP-9 silencing regulates hTERT expression via ?1 integrin-mediated FAK signaling and induces senescence in glioma xenograft cells. Cell Signal 23:2065-75|
|Ponnala, Shivani; Veeravalli, Krishna Kumar; Chetty, Chandramu et al. (2011) Regulation of DNA repair mechanism in human glioma xenograft cells both in vitro and in vivo in nude mice. PLoS One 6:e26191|
|Veeravalli, Krishna Kumar; Chetty, Chandramu; Ponnala, Shivani et al. (2010) MMP-9, uPAR and cathepsin B silencing downregulate integrins in human glioma xenograft cells in vitro and in vivo in nude mice. PLoS One 5:e11583|
|Chetty, Chandramu; Lakka, Sajani S; Bhoopathi, Praveen et al. (2010) Urokinase plasminogen activator receptor and/or matrix metalloproteinase-9 inhibition induces apoptosis signaling through lipid rafts in glioblastoma xenograft cells. Mol Cancer Ther 9:2605-17|
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