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）均为CD 44配体，在MPM的胸腔积液和组织中高度表达，可能参与了MPM的发病机制。然而，CD 44、OPN和HA的确切作用，特别是在MPM的多药耐药中的作用，仍有待阐明。因此，我们建立了稳定的人间皮瘤细胞系（ACC-MESO-1/OPN），组成型表达OPN，以确定其在MPM中观察到的化疗耐药性中的作用。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。在ACC. MESO中，抑制HA结合的CD 44变体同种型的表达显著降低。1/OPN细胞与对照转染子相比。有趣的是，HA-CD 44相互作用的抑制消除了ACC. MESO中的多药耐药性。1/OPN，因此表明HA-CD 44相互作用产生的存活信号的参与。ACC. MESO.观察到1/OPN细胞，并且被CD 44 siRNA减少。抑制Akt磷酸化可增加化疗药物如NVB、VP-16和GEM诱导的细胞凋亡数量。总的来说，这些结果表明OPN通过增强CD 44与HA的结合而强烈参与多药耐药性。抑制CD 44、OPN和HA之间的相互作用可能是MPM患者有希望的治疗策略之一。

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.