The development of resistance to chemotherapeutic drugs is a serious problem in the treatment of cancer. Paclitaxel (Taxol) is a microtubule-binding drug used in the treatment of ovarian adenocarcinomas. Unfortunately, many ovarian cancer patients will become resistant to the drug, which makes the development of alternative or secondary therapies important. Recently, the large GTPase, human Guanylate-Binding Protein-1 (hGBP-1) was shown to be up-regulated in MCF-7 breast cancer cells and SKOV3 and OVCAR8 ovarian cancer cell lines when they were made resistant to paclitaxel by continuous culture in the drug. Forced expression of hGBP-1 in OVCAR8, SKOV3, or MCF-7 cells confers resistance to paclitaxel in vitro. These data suggest that hGBP-1 might make a good marker for the development of paclitaxel resistance. Whether hGBP-1 confers paclitaxel resistance in vivo will be analyzed using a mouse xenograft model of human ovarian cancer cell lines with regulated expression of hGBP-1. We will also examine whether the expression of hGBP- 1 is associated with the development of paclitaxel resisitance in women with ovarian cancer. In addition, characterization of the molecular mechanism(s) by which hGBP-1 confers resistance to paclitaxel could ultimately provide therapeutic tools to either prevent the resistance to paclitaxel or inhibit it by targeting hGBP- 1 itself. It is known that hGBP-1 alters gene expression in endothelial cells and we will explore the possibility that hGBP-1 alters the expression of a profile of apoptosis-related genes induced by paclitaxel. Identification of a new marker for resistance might give physicians another tool for mananging patient treatment. It would allow switching to a new drug earlier, preventing the wasting of time with a drug to which the patient has stopped responding. Analysis of the activity of hGBP-1 might ultimately provide a target for overcoming this resistance.

Public Health Relevance

Resistance to the chemotherapeutic drug, paclitaxel, is a major problem in the treatment of ovarian cancer. Recently a putative new mechanism for paclitaxel resistance in vitro was discovered, the up-regulation of human GBP-1. The evaluation of hGBP-1 as both a marker for paclitaxel resistance and a possible therapeutic target may contribute to novel therapies to improve patient survival.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Fu, Yali
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University of Toledo
Schools of Arts and Sciences
United States
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Wadi, Suzan; Tipton, Aaron R; Trendel, Jill A et al. (2016) hGBP-1 Expression Predicts Shorter Progression-Free Survival in Ovarian Cancers, While Contributing to Paclitaxel Resistance. J Cancer Ther 7:994-1007
Tipton, Aaron R; Nyabuto, Geoffrey O; Trendel, Jill A et al. (2016) Guanylate-Binding Protein-1 protects ovarian cancer cell lines but not breast cancer cell lines from killing by paclitaxel. Biochem Biophys Res Commun 478:1617-23
Vestal, Deborah J; Jeyaratnam, Jonathan A (2011) The guanylate-binding proteins: emerging insights into the biochemical properties and functions of this family of large interferon-induced guanosine triphosphatase. J Interferon Cytokine Res 31:89-97