Molecular Mechanisms of Cancer Origination and Progression, Focusing on PTEN
Dimpy Koul, Ph.D.
My research focuses on the molecular mechanisms of cancer initiation and progression, particularly through analysis of the role of the PTEN gene. Mutations of PTEN, a tumor suppressor located on chromosome 10, are prevalent in various human cancers, including glioblastoma, and our laboratory is analyzing the biochemical pathways and molecular mechanisms that are responsible for PTEN’s involvement in regulation of apoptosis, cell cycle entry, proliferation and invasion. We have shown that PTEN specifically decreases cell signaling through the phosphatidylinositol 3-kinase (PI3K) pathway by various mechanisms, leading to increased rates of anoikis and programmed cell death. These effects suggest that PTEN acts as a tumor suppressor by promoting apoptosis, and PTEN inactivation may induce tumor proliferation and metastasis.
The role of PTEN in regulating AP-1 and NFkB, two key transcription factors that are required for tumor development, and in the sensitization of glioma cells to TNF-induced apoptosis is another area of interest, with a goal of characterizing the signaling mechanism that is involved in PTEN’s relationship with NFkB and AP-1. A major part of TNF-induced cytoprotection is attributed to the activation of NFkB. Activated NFkB induces the expression of multiple proteins that protect against cell death, and Akt has been shown to be necessary for the activation of the p65 subunit of NFkB. PTEN blocks TNF-stimulated NFkB-dependent gene transcription and sensitize cells to TNF-induced cell killing.
Since PTEN regulation is complex, significant effort is directed to characterizing proteins that interact with PTEN to form putative signaling complexes. Because PTEN likely regulates multiple PI3K family members, I have focused on functions that are related to oncogenesis, and identified one of these proteins, hDlg. We found that loss of function mutations of Dlg result in the neoplastic overgrowth of imaginal discs and larval lethality in drosophila. Characterizing the associations between the PTEN signaling complex and tyrosine phosphorylation should help us understand PTEN functioning and devise interventions to restore normal function. Our research includes finding antitumor therapeutic tools based on modification of PTEN’s enzymatic activity in cancer cells.
Koul D, Shen R, Shishodia S, Takada Y, Bhat KP, Reddy SA, Aggarwal BB, Yung WK. PTEN down regulates AP-1 and targets c-fos in human glioma cells Via PI3-kinase/Akt pathway. Mol Cell Biochem, 2007.
Koul D, Takada Y, Shen R, Aggarwal BB, Yung WK. PTEN enhances TNF-induced apoptosis through modulation of nuclear factor-kappaB signaling pathway in human glioma cells. Biochem Biophys Res Commun 350: 463-471, 2006.
Koul D, Shen R, Bergh S, Sheng X, Shishodia S, Lafortune TA, Lu Y, de Groot JF, Mills GB, Yung WK. Inhibition of Akt survival pathway by a small-molecule inhibitor in human glioblastoma. Mol Cancer Ther 5: 637-644, 2006.
Koul D, Shen R, Bergh S, Lu Y, de Groot JF, Liu TJ, Mills GB, Yung WK. Targeting integrin-linked kinase inhibits Akt signaling pathways and decreases tumor progression of human glioblastoma. Mol Cancer Ther 4: 1681-1688, 2005.
Nigro JM, Misra A, Zhang L, Smirnov I, Colman H, Griffin C, Ozburn N, Chen M, Pan E, Koul D, Yung WK, Feuerstein BG, Aldape KD. Integrated array-comparative genomic hybridization and expression array profiles identify clinically relevant molecular subtypes of glioblastoma. Cancer Res. 2005 Mar 1;65(5):1678-86.
Cerrato JA, Khan T, Koul D, Lang FF, Conrad CA, Yung WK, Liu TJ. Differential activation of the Fas/CD95 pathway by Ad-p53 in human gliomas. Int J Oncol. 2004 Feb;24(2):409-17.
Lu Y, Yu Q, Liu JH, Zhang J, Wang H, Koul D, McMurray JS, Fang X, Yung WK, Siminovitch KA, Mills GB. Src family protein-tyrosine kinases alter the function of PTEN to regulate phosphatidylinositol 3-kinase/AKT cascades. J Biol Chem. 2003 Oct 10;278(41):40057-66. Epub 2003 Jul 17.
Koul D, Shen R, Garyali A, Ke LD, Liu TJ, Yung WK. MMAC/PTEN tumor suppressor gene regulates vascular endothelial growth factor-mediated angiogenesis in prostate cancer. Int J Oncol. 2002 Sep;21(3):469-75.
Koul D, Jasser SA, Lu Y, Davies MA, Shen R, Shi Y, Mills GB, Yung WK. Motif analysis of the tumor suppressor gene MMAC/PTEN identifies tyrosines critical for tumor suppression and lipid phosphatase activity. Oncogene. 2002 Apr 4;21(15):2357-64.