SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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T U M O R C E L L B I O L O G Y P R O G R A M • Development of a novel thermodynamically balanced inside-out method of polymerase chain reaction (PCR)-based synthesis to generate codon-optimized human kinase genes (T. Harris). • VegT, a T-box transcription factor, is essential for three important steps in development (M. L. King). • Glycolytic inhibitors can be used to specifically target the hypoxic slow-growing cells of solid tumors and thereby increase the efficacy of current chemotherapeutic and irradiation protocols designed to kill rapidly dividing cells (T. Lampidis). • In osteosarcoma, the addition of the glycolytic inhibitor 2-Deoxyglucose (2-DG) increases the efficacy of Adriamycin in reducing tumor size and prolonging survival (T. Lampidis). • In non-small cell lung cancer, the addition of 2- DG increases the effectiveness of taxol (T. Lampidis). • Microvascular endothelial cells produce two extracellular matrix proteins, laminin-8 and laminin-10, which play important roles in tumor angiogenesis (J. Li). • Discovery of an imbalance between the levels of matrix metalloproteinases (MMPs) (overproduction) and their natural inhibitors (underproduction) in invasive prostate cancer cells (B. Lokeshwar). • Identification of a novel chemically modified non-antimicrobial tetracycline (COL-3) as an effective anti-metastatic drug with the potential to treat prostate cancer metastatic to bone; completion of NCI phase I trial of this drug (B. Lokeshwar). • Development of the HA-HAase urine test, a non-invasive test that is about 90 percent accurate in detecting bladder cancer and monitoring its recurrence (V. Lokeshwar). • Development of HA and HAase tests that are greater than 85 percent accurate prognostic indicators for prostate cancer (V. Lokeshwar). • Demonstration of the function of tumor-derived HAase in bladder tumor growth and muscle invasion (V. Lokeshwar). • Splicing activator RNPS1 is incorporated in the early splicing complex, stimulating formation of the ATP-dependent splicing complex, and subsequently increasing generation of both intermediate and final spliced products (A. Mayeda). • Cells with defective mitochondrial respiration can be more resistant to cell death, which might explain the presence of mtDNA mutations in some cancers (C. Moraes). • Mitochondrial defects stimulate the production of metalloproteases, which in turn promotes tissue invasion (C. Moraes). • Up-regulation of ErbB2 ligand Muc4 expression correlates with the overexpression of transcription factor PEA3 and the receptor tyrosine kinase ErbB2 (A. Perez). • Observation of the attachment of centrosomes to intermediate filaments (P. Salas). • Nerve growth factor (NGF) mediates the invasiveness of melanoma cells in vitro by inducing the coupling of the intracellular domain of the p75 neurotrophin receptor with the actin cytoskeleton (O. Shonukan). • Neurotrophin-induced melanoma invasiveness is mediated by signals generated through PI-3 kinase (O. Shonukan). • NGF induces the disruption of cadherin-mediated cell-cell adhesion, thereby permitting melanoma cells to dissociate from the keratinocytes in the epidermis, and invade the dermis, from whence they metastasize to distant sites (O. Shonukan). • Aberrant p27 in breast cancer cells causes them to be unable to respond to antiestrogen therapies such as Tamoxifen (J. Slingerland). • Activation of the Src pathway is linked with both the lack of detectable estrogen receptor (ER) and clinically aggressive behavior of breast cancers (J. Slingerland). UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 67
T U M O R C E L L B I O L O G Y P R O G R A M • Discovery of estrogen regulation of the gap junction protein connexin 43 via an internal ribosome entry site for translation (R. Werner). • Discovery of the requirement for Rho family GTPases for key adhesion-dependent G1 events, including cyclin D1 expression, Rb phosphorylation, and cyclin A expression (C. Welsh). KERRY L. BURNSTEIN, PH.D. Professor of Molecular and Cellular Pharmacology DESCRIPTION OF RESEARCH Dr. Burnstein’s research focuses on signaling mechanisms that govern prostate cancer cell cycle and androgen responsiveness. Vitamin D is of particular interest, stemming from epidemiological data showing a relationship between vitamin D deficiency and increased risk of prostate cancer mortality. It has been shown that vitamin D inhibits the growth of prostate cancer cell lines and primary cell cultures derived from human prostate tumors. Researchers in Dr. Burnstein’s laboratory found that the mechanism underlying such growth arrest is a vitamin D-induced cellular accumulation in the initial phase of the cell cycle, G1. They demonstrated that vitamin D- mediated antiproliferative effects are not dependent on androgen/AR. This finding is of clinical relevance, as a requirement for androgen would severely limit use of vitamin D in advanced prostate cancer, which is customarily treated by androgen ablation. Furthermore, Dr. Burnstein’s laboratory showed that vitamin D causes upregulation of specific and potent cell cycle inhibitors, p21 and p27, a finding that has potentially important therapeutic implications. Her laboratory recently made the novel discovery that vitamin D mediates the nuclear exclusion of cyclin dependent kinase (cdk)-2, thereby decreasing its activity and promoting p27 stability. Current efforts are directed at understanding vitamin D regulation of cdk-2 nucleocytoplasmic trafficking. A finding that emerged from the studies on vitamin D was that the most highly malignant prostate cancer cell lines expressed very low levels of cdk inhibitors. Subsequent studies on human prostate cancer biopsies confirmed this observation. Because of these findings and the fact that the genes encoding these inhibitors are rarely mutated, Dr. Burnstein decided to investigate possible intracellular signaling alterations that might suppress levels of these inhibitory proteins and contribute to uncontrolled cell proliferation. In collaboration with Catherine F. Welsh, M.D., she made the novel observation that Rac1, a Ras-related Rho GTPase (small G protein), exhibits high activity in the more malignant prostate cancer cells. Specific inhibition of Rac1 in these cells results in increased levels of the cdk inhibitor p21 and decreased proliferation. These findings are unique in describing a role for Rac1 in the regulation of p21 and implicate the Rac1 signaling pathway as a therapeutic target. Recently, researchers found that a protein that activates Rac1 also enhances the transcriptional activity of the androgen receptor (AR). This observation provides a tantalizing link between two critical signaling pathways in prostate cancer and suggests a plausible mechanism for AR activity during progression to androgen independence. SELECTED PUBLICATIONS 2002 Yang, ES, Maiorino, CA, Roos, BA, Knight, SR, and Burnstein, KL . Vitamin D-mediated growth inhibition of an androgen-ablated LNCaP cell line model of human prostate cancer. Molecular and Cellular Endocrinology 186:69-79, 2002. Whitlatch, LW, Young, MV, Schwartz, GG, Flanagan, JN, Burnstein, KL , Lokeshwar, BL, Rich, ES, Holick, MF, and Chen, TC. 25- Hydroxyvitamin D-1alpha-hydroxylase activity is diminished in human prostate cancer cells and is enhanced by gene transfer. Journal of Steroid Biochemistry and Molecular Biology 81:135-40, 2002. 68 UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
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G L O S S A R Y IFN—interferon IL
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SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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