Regulation of MDR1 Expression and Drug Resistance by CD44

描述（由申请人提供）：转移和耐药性是癌症治疗失败的主要原因。这两个重要的，但不明确相关的癌症生物学方面已被广泛研究，但只有间接的证据表明，表型可能是功能上的联系。两种蛋白质，P-糖蛋白（P-gp）和CD 44，是众所周知的决定因素，分别多药耐药和转移。P-gp是MDR 1（ABCB 1）基因的产物，是一种跨膜ATP依赖性转运蛋白，可使癌细胞产生耐药性。CD 44是一种与细胞粘附、运动性和转移有关的膜蛋白，是透明质酸的主要受体，透明质酸是在所有类型的哺乳动物细胞外基质（例如卵巢癌转移最重要的部位腹膜）中发现的主要糖胺聚糖。当研究CD 44在肿瘤转移中的作用时，我们意外地发现了两种独立但可能相互关联的机制，将CD 44和P-gp在耐药中联系起来：CD 44与P-gp物理相互作用，CD 44激活MDR 1和P-gp表达，并且这种诱导依赖于CD 44 Ser 291磷酸化。该机制似乎是转录的，因为初步数据显示，将CD 44引入空细胞激活MDR 1启动子构建体。然而，确切的机制尚不清楚。目前还不清楚通过这种蛋白质-蛋白质相互作用导致耐药性增加的机制是什么。我们的总体目标是研究耐药性发展的机制。具体来说，我们将实现以下目标：1）研究CD 44调节MDR 1表达和P-gp功能的机制。1A.验证CD 44与P-gp相互作用的生理/药理学意义。1B.确定CD 44调节MDR 1转录的机制。2)研究CD 44表达对体内化疗耐药性的影响。1A.在卵巢癌小鼠异种移植模型中检测CD 44在耐药性中的作用。2B.目的探讨卵巢癌患者CD 44和P-gp的双重表达是否是卵巢癌耐药的预测指标。

DESCRIPTION (provided by applicant): 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.