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 ELIZABETH J. FRANZMANN, M.D. Assistant Professor of Otolaryngology DESCRIPTION OF RESEARCH Dr. Franzmann is interested in the molecular mechanisms of head and neck squamous cell cancer (HNSCC) progression. Despite rigorous therapy using various combinations of surgery, radiation, and chemotherapy, successful treatment of head and neck cancer only occurs 50 percent of the time. Because of the complexity of the head and neck, current therapy often results in facial disfigurement, speech and swallowing problems, and substantial health care costs. Screening and staging methods for HNSCC also are deficient. To better understand the molecular mechanisms that lead to HNSCC, Dr. Franzmann’s laboratory is investigating the CD44 family of alternatively spliced isoforms. Some CD44 isoforms are found normally in cells. Other isoforms termed CD44 variant (CD44v) isoforms are found in tumor tissues and are associated with poor prognosis. There is particular interest in the CD44v3-containing isoforms since these isoforms contain a growth factor binding site. Preliminary work suggests that CD44v3-containing isoforms are differentially expressed in HNSCC tumors and normal tissue and may be involved in tumor cell growth. Using reverse transcriptase-polymerase chain reaction (RT- PCR), southern blot, cloning, and sequencing, the laboratory is defining CD44v3-containing isoform expression in head and neck tumor and normal tissues. The laboratory will perform immunohistochemical staining to characterize CD44v3 expression at the protein level. Transfection studies will be used to investigate the mechanisms by which these isoforms alter HNSCC cell behavior. In addition to identifying HNSCC in the early stage when treatment is much more effective, Dr. Franzmann’s laboratory is evaluating whether a salivary CD44 ELISA test is a useful screening tool for HNSCC. SELECTED PUBLICATIONS 2003 Franzmann, EJ, Schroeder, GL, Goodwin, WJ, Weed, DT, Fisher, P, and Lokeshwar, VB. Expression of tumor markers hyaluronic acid and hyaluronidase (HYAL1) in head and neck tumors. International Journal of Cancer 106:438-45, 2003. HIGHLIGHTS/DISCOVERIES • CD44v3-containing isoforms are found in HNSCC tumor tissues and cell lines using RT- PCR. CD44v3 and CD44v3-10 have been cloned and sequenced from HNSCC cell lines. • In a preliminary study including 26 patients with HNSCC and ten normal controls, CD44 levels were significantly higher in HNSCC patient saliva compared to normal volunteer saliva. ZHIYONG HAN, PH.D. Assistant Professor of Biology DESCRIPTION OF RESEARCH Dr. Han’s research seeks to understand how anti-cancer drugs induce apoptosis of cancer cells. His recent work focuses on how the natural product camptothecin (CPT) and its semi-synthetic derivatives such as CPT-11, 9-amino-CPT (9AC), and 9-nitro-CPT (9NC) induce apoptosis of human colon cancer cells. CPT and its derivatives are considered important anti-cancer drugs. Many aspects of the mechanism by which these drugs exert their death effect on cancer cells, however, remain largely unknown. In recent years, Dr. Han and his colleagues have used a cell model of human colon cancer to demonstrate that treatment with low doses of CPT induces senescence in the presence of a protein called p21, but apoptosis in the absence of p21. Therefore, p21 is a key determinant of the outcome of colon cancer cells treated with CPT drugs at doses that are relevant to clinical application. CPT treatment of colon cancer cells with p21 should result in disease stabili- UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 75
T U M O R C E L L B I O L O G Y P R O G R A M zation, whereas CPT treatment of p21-deficient colon cancer cells should result in rapid apoptosis and disease regression. It is well established that p21 inhibits cyclindependent kinases (cdks) and several other factors including proliferating cell nuclear antigen. Dr. Han and his colleagues hypothesize that inhibition of cdks by p21 is essential to inhibit apoptosis and induce senescence. In this context, they propose that the protein, named E2F1, is essential for apoptosis of colon cancer cells treated with CPT. According to this hypothesis, inhibition of cdks should result in activation of another protein, named retinoblastoma (Rb), which in turn, inhibits E2F1 and consequentially E2F1-dependent apoptosis. They also hypothesize that the ability of p21 to induce senescence requires a protein called STAT1. To test their hypothesis, they are currently using techniques to selectively alter the status of a cdk, E2F1, Rb, and STAT1 in human colon cancer cells. Subsequently, Dr. Han’s laboratory will investigate the role of each protein in the process of apoptosis and senescence in the colon cancer cells after CPT treatment. The information obtained from these investigations will provide better insight into the molecular pathways activated in colon cancer cells after CPT treatment and eventually lead to specific experimental designs to completely understand how CPTs affect colon cancer. SELECTED PUBLICATIONS 2002 Han, Z, Wei, W, Dunaway, S, Darnowski, JW, Calabresi, P, Sedivy, J, Hendrickson, EA, Balan, KV, Pantazis, P, and Wyche, JH. Role of p21 in apoptosis and senescence of human colon cancer cells treated with camptothecin. Journal of Biological Chemistry 277(19):17154-60, 2002. 2003 Hu, X, Han, Z, Wyche, JH, and Hendrickson, EA. Helix 6 of tBid is necessary but not sufficient for mitochondrial binding activity. Apoptosis 8:277-89, 2003. Pantazis, P, Han, Z, Balan, K, Wang, Y, and Wyche, JH. Camptothecin and 9- nitrocamptothecin (9NC) and anti-cancer, anti-HIV, and cell-differentiation agents. Development of resistance, enhancement of 9NC-induced activities and combination treatments in cell and animal models. Anticancer Research 23:3623-38, 2003. Hu, X, Balan, KV, Ramos-DeSimone, N, Wyche, JH, Han, Z, and Pantazis, P. Differential susceptibility to 9-nitrocamptothecin (9-NC)-induced apoptosis in clones derived from a human ovarian cancer cell line: possible implications in the treatment of ovarian cancer patients with 9-NC. Anticancer Drugs 14:427-36, 2003. THOMAS K. HARRIS, PH.D. Assistant Professor of Biochemistry and Molecular Biology DESCRIPTION OF RESEARCH Dr. Harris’ research seeks to understand the structure and mechanism of both phosphoinositide-dependent protein kinase (PDK1) and protein kinase B (PKB/Akt), which are important in maintaining the growth, survival, and proliferation of numerous types of cancer cells. PDK1 and PKB/Akt are pivotal signaling enzymes and are activated by growthfactor binding events to receptor tyrosine kinases, which activate phosphatidylinositol 3-kinase (PI3K) and result in generation of the membrane-bound second messenger phosphatidylinositol 3,4,5- triphosphate. Activation of PDK1 and PKB/Akt is facilitated by recruitment of each of these proto-oncogenic enzymes to the membranebound second messenger, which binds the pleckstrin homology (PH) domain present in each of these kinases. The specific goals are to 1) determine the structural bases of specificity for membrane targeting mediated by the PH domains of human PDK1 and PKB/Akt, and 2) determine how binding of the PH domains to 76 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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