Mechanism of multidrug resistance in mesothelioma cells, and the treatment strategy targeting CD44

恶性胸膜间皮瘤(MPM)对化疗有抵抗力，因此预后很差。骨桥蛋白(OPN)和透明质酸(HA)都是CD44的配体，在MPM的胸腔积液和组织中高度表达，提示它们参与了MPM的发病机制。然而，CD44、OPN和HA在MPM多药耐药中的确切作用仍有待阐明。因此，我们建立了稳定表达OPN的人间皮瘤细胞系(ACC-Meso-1/OPN)，以确定其在MPM化疗耐药中的作用。OPN基因的引入通过增强HA结合的机制为MPM细胞提供了上调的多药耐药性。抑制HA结合的CD44异构体在ACC中的表达显著降低。梅索。1/OPN细胞与对照组比较。有趣的是，HA-CD44相互作用的抑制消除了ACC的多药耐药性。梅索。1/OPN，提示HA-CD44相互作用中的存活信号参与其中。在ACC中，p-Akt的水平升高。梅索。1/OPN细胞被CD44 siRNA抑制。抑制Akt的磷酸化增加了化疗药物NVB、VP-16和GEM诱导的细胞凋亡。总之，这些结果表明，OPN通过增强CD44与HA的结合而强烈参与多药耐药。抑制CD44、OPN和HA之间的相互作用可能是治疗MPM的有前途的策略之一。

Malignant pleural mesothelioma(MPM) is resistant to chemotherapy and thus shows a dismal prognosis. Osteopontin(OPN) and hyaluronate(HA), both of which are CD44 ligands, are highly detected in the pleural effusion and tissues of MPM, and suggested to be involved in the pathogenesis of MPM. However, the precise role of CD44, OPN, and HA, especially in the multidrug resistance of MPM, remains to be elucidated. We therefore established stable transfectants(ACC-MESO-1/OPN) of human mesothelioma cell line, which constitutively express OPN, to determine its role in the chemoresistance observed in MPM. The introduction of the OPN gene provides MPM cells with upregulated multidrug resistance through the mechanism of enhanced HA binding. The expression of CD44 variant isoforms, which inhibit HA binding, significantly decreased in ACC. MESO. 1/OPN cells in comparison to control transfectants. Interestingly, the inhibition of the HA-CD44 interaction abrogated multidrug resistance in the ACC. MESO. 1/OPN, thus suggesting the involvement of the surviving signal emanating from the HA-CD44 interaction. An enhanced level of the p-Akt in ACC. MESO. 1/OPN cells was observed, and was diminished by CD44 siRNA. Inhibition of the Akt phosphorylation increased in number of the cells underwent apoptosis induced by chemotherapeutic drugs, such as NVB, VP-16 and GEM. Collectively, these results indicate that OPN is strongly involved in multidrug resistance by enhancing the CD44 binding to HA. Inhibition of interaction between CD44, OPN, and HA, may be one of the promising treatment strategy for patients with MPM.