Metastases and drug resistance are the major causes of treatment failure in cancer. These two important but not clearly related aspects in the biology of cancer have been extensively studied, but there is only indirect evidence that the phenotypes may be functionally linked. Two proteins, P-glycoprotein (P-gp) and CD44, are well known determinants of multidrug resistance and metastases, respectively. P-gp, the product of the MDR1 (ABCB1)-gene, is a transmembrane ATP-dependent transporter that confers drug resistance to cancer cells. CD44 is a membrane protein implicated in cell adhesion, motility and metastases and is the major receptor for hyaluronan, the principal glycosaminoglycan found in all types of mammalian extracellular matrices, such as the peritoneum, the most important site for ovarian cancer metastases. When studying the role of CD44 in cancer metastases, we unexpectedly uncovered two separate but possibly interrelated mechanisms linking CD44 and P-gp in drug resistance: CD44 physically interacts with P-gp and CD44 activates MDR1 and P-gp expression and this induction is dependent of CD44 Ser 291 phosphorylation. The mechanism appears to be transcriptional, since preliminary data shows that introduction of CD44 into null cells activates an MDR1 promoter construct. However the exact mechanism is not known. It is also unclear what is the mechanism that leads to increase drug resistance through this protein-protein interaction. Our overall goal is to investigate the mechanisms responsible for the development of drug resistance. Specifically, we will address the following aims: 1) To investigate mechanisms by which CD44 regulates MDR1 expression and P-gp function. 1A. To verify the physiological/pharmacological significance of the interactions between CD44 and P-gp. 1B. To determine the mechanism by which CD44 regulates MDR1 transcription. 2) To study the impact of CD44 expression on in vivo chemoresistance. 1A. To test the effect of CD44 in drug resistance in an ovarian cancer mouse xenograft model. 2B. To determine whether the dual expression of CD44 and P-gp is a predictive marker for drug resistance in women with ovarian cancer.
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