Isa M. Hussaini, Ph.D.

Associate Professor of Pathology and Neuroscience

RESEARCH:

The prognosis for patients with malignant astroglial tumors is poor. The capacity of astrocytomas both to invade adjacent brain sites and to migrate into distant ones precludes curative surgical resection; and little progress has been made in designing adjuvant therapies that significantly affect long-term survival. In order to formulate more novel therapeutic strategies, it is essential to have a better understanding of how the invasive growth of these tumors is controlled.

The primary interest of the laboratory is the regulation of LRP (low density lipoprotein receptor-related protein) expression and function in astrocytic tumor cells. LRP is an endocytic receptor involved in the trafficking of a variety of protein/protein complexes that have pathophysiologic relevance in the central nervous system, including urokinase (uPA) and its receptor (uPAR), lipoprotein metabolites, and activated alpha2-macroglobulin. Changes in LRP expression may regulate the levels of modulators (uPA, uPAR and PAI-1) of migration/invasion around the microenvironment of astrocytic tumors.

The second project in my laboratory focuses on understanding differences in PKC-eta activation and expression between malignant vs. non-neoplastic astrocytes and on the role of PKC-eta in the control of cell proliferation and apoptosis. The regulation of cell proliferation and apoptosis in malignant astrocytic tumors is undoubtedly complex; however, we are investigating how PKC-eta regulation of these processes may be exploited to provide an experimental system in which proliferative or apoptotic phenotype may be selectively induced and studied. We are also extrapolating some of our results in cultured cells to glioblastoma animal models. We hypothesize that pharmacological regulation of PKC-eta, in combination with drugs targeting cellular migration, may present a new therapeutic paradigm for these aggressive brain tumors.

REFERENCES:

• Hussaini, I.M., Karns, L.R., Griffith, V., Carpenter, J.E., Redpath, G.T., Sando, J.J. and VandenBerg, S.R. (2000). Phorbol 12-myristate-13-acetate induces protein kinase C-η-specific proliferative response in astrocytic tumor cells. J. Biol. Chem. 275: 22348-22354.
• Goldfarb, A.N., Delehanty, L.L., Wang, D., Racke, F.K. and Hussaini, I.M. (2001). Stromal inhibition of megakaryocytic differentiation correlates with blockade of signaling by PKC-ε and ERK/MAPK. J. Biol. Chem. 276: 29526-29530.
• Hussaini, I.M., Carpenter, J.E., Redpath, G.T Sando, J.J., Shaffrey, M.E. and VandenBerg, S.R (2002). Protein kinase C-η regulates resistance to UV- and γ-Irradiation-induced apoptosis by preventing caspase-9 cleavage in astrocytomas.  Neuro-Oncology 4(1): 9-13.
• Aeder, S.E., Martin P.M., Soh J-W. and Hussaini, I.M. (2004) PKC-η Mediates Glioblastoma Cell Proliferation Through the Akt and mTOR Signaling Pathways. Oncogene 23:9062-9069.
• Amos S, Martin PM, Polar GA, Parsons SJ, Hussaini IM. (2005). Phorbol 12-myristate 13-acetate induces epidermal growth factor receptor transactivation via protein kinase C delta/c-Src pathways in glioblastoma cells. J. Biol. Chem. 280(9):7729-38.
• Amos, S, Redpath, GT, Polar, G, McPheson, R, Schiff D and Hussaini IM (2006). Farnesylthiosalicylic Acid Induces Caspase Activation and Apoptosis in Glioblastoma Cells. Cell Death and Differentiation, 13(4):642-51.
• Abdel-Fattah, R., Xiao, A., Bomgardner D., Clinton-Scott, P., Lopes M-B. S. and Hussaini, I.M. (2006) Differential Expression of HOX genes in Neoplastic and Non-neoplastic human astrocytes.  The Journal of Pathology. 209(1):15-24.
• Martin PM, Aeder, SE, Chrestensen, AC, Sturgill, TW and Hussaini IM (2007) Phorbol Ester Induced Rapamycin Insensitive Cell Proliferation is Regulated by Protein Kinase C-η. Oncogene, 26(3):407-14
• Hussaini IM, Trotter, C, Zhao, Y, Abdel-Fattah R, Amos, S, Xiao, A, Agi CU, Redpath, GT, Fang Z, Gilberto LKK, Lopes BS, Laws ER (2007) Differential Invasion-associated DNA Microarray Gene Expression Profiles in Non-functioning Pituitary Adenomas: The Role of MMP-9 in Pituitary Adenoma Invasion, Am J Pathol. 170(1):356-65.
• Uht, RM, Martin, PP, Riggan AE and Hussaini IM (2007) The Protein Kinase C-η Induces Proliferaion in Glioblastoma Cell Lines trough an ERK/Elk-1 Pathway Oncogene, 26(20):2885-2893.
• Amos, S.,  diPierro CG,  Carpenter, JE, Xiao, A, Kohutek, Z,  Redpath, GT,  Zhao, Y,  Wang, J, Mut, M, Shaffrey ME and Hussaini, IM (2007) Protein Kinase C-α -mediated regulation of Low Density Lipoprotein Receptor Related Protein and urokinase increases Astrocytoma Invasion. Cancer Research 67: 10241-10251.
• Zhao Y, Xiao A, Dipierro CG, Abdel-Fattah R, Amos S, Redpath GT, Carpenter JE, Pieper RO, Hussaini IM. (2008) H-Ras increases urokinase expression and cell invasion in genetically modified human astrocytes through Ras/Raf/MEK signaling pathway. Glia. 56(8):917-24.
• Li Y, Guessous F, Kwon S, Kumar M, Ibidapo O, Fuller L, Johnson E, Lal B, Hussaini I, Bao Y, Laterra J, Schiff D, Abounader R (2008) PTEN has tumor-promoting properties in the setting of gain-of-function p53 mutations. Cancer Res. 68(6):1723-31.