Regulation of multidrug resistance in cancer cells by hyaluronan
Regulation of multidrug resistance in cancer cells by hyaluronan
复制标题
DOI：
10.1074/jbc.c300173200
复制
发表时间：
2003-07-11
影响因子：
4.8
通讯作者：
Toole, BP
中科院分区：
文献类型：
--
作者：
Misra, S;Ghatak, S;Toole, BP
癌细胞的多药耐药通常是由于依赖于ATP的外排泵，但也与细胞存活和凋亡信号通路的变化有关。我们先前已经发现，透明质酸低聚糖干扰透明质酸与肿瘤细胞的相互作用会抑制癌细胞中的肌醇磷脂3-激酶/Akt细胞生存信号通路，从而减少体内肿瘤的生长。在这里，我们发现这些寡聚体抑制多药耐药肿瘤细胞中的MAP激酶和磷脂酰肌醇3-激酶通路，并使这些细胞对各种化疗药物敏感。另一方面，透明质酸产量的增加会导致对药物敏感的肿瘤细胞产生耐药性。同样，Emmprin的表达增加，这是一种存在于大多数恶性肿瘤细胞表面的糖蛋白，可以刺激透明质酸的产生，也会导致耐药性的增加。因此，干扰透明质酸信号可能具有双重治疗作用，因为它对肿瘤生长具有内在的抑制作用，同时也使癌细胞对化疗药物敏感。
Multidrug resistance in cancer cells is often due to ATP-dependent efflux pumps, but is also linked to alterations in cell survival and apoptotic signaling pathways. We have found previously that perturbation of hyaluronan-tumor cell interaction by treatment with hyaluronan oligosaccharides suppresses the phosphoinositide 3-kinase/Akt cell survival signaling pathway in cancer cells and reduces tumor growth in vivo. Here we find that these oligomers suppress both the MAP kinase and phosphoinositide 3-kinase pathways in multidrug resistant tumor cells and sensitize these cells to a variety of chemotherapeutic drugs. On the other hand, increased hyaluronan production induces resistance in drug-sensitive tumor cells. Likewise, increased expression of emmprin, which is a glycoprotein that is present on the surface of most malignant cancer cells and that stimulates hyaluronan production, also induces increased resistance. Thus, perturbation of hyaluronan signaling may provide a dual therapeutic role, since it has intrinsic suppressive effects on tumor growth as well as sensitizing cancer cells to chemotherapeutic agents.