Up-regulation of CD147 and matrix metalloproteinase-2,-9 induced by P-glycoprotein substrates in multidrug resistant breast cancer cells
Up-regulation of CD147 and matrix metalloproteinase-2,-9 induced by P-glycoprotein substrates in multidrug resistant breast cancer cells
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DOI：
10.1111/j.1349-7006.2007.00593.x
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发表时间：
2007-11-01
期刊：
影响因子：
5.7
通讯作者：
Xu, Zu-De
中科院分区：
文献类型：
--
作者：
Li, Qing-Quan;Wang, Wen-Juan;Xu, Zu-De
用P-糖蛋白(P-gp)底物治疗携带多药耐药(MDR)肿瘤细胞的动物可能会恶化宿主的存活率。据推测，这是由于肿瘤转移增加所致。为了阐明这一观察结果的机制(S)，在无血清培养中，用不同浓度的P-gp底物药物(长春新碱、紫杉醇、阿霉素)和P-gp非底物药物(博莱霉素)处理多药耐药人乳腺癌细胞株MCF-7/AdrR及其敏感亲本株MCF-7。实时聚合酶链式反应、免疫印迹和酶谱检测显示，只有暴露于P-gp底物的多药耐药癌细胞CD147和基质金属蛋白酶(MMP)-2、-9的表达增加。相应地，P-gp底物显著增强了MCF-7/ADR细胞的体外侵袭能力。药物诱导CD147、MMP2、9的上调与表皮生长因子受体(EGFR)表达的增加是一致的，抑制EGFR或P-gp的活性均可显著阻断其下游效应，从而抑制P-gp底物的体外侵袭能力。这些结果表明，P-gp底物治疗MDR肿瘤可能通过调节CD147、MMP-2、-9和EGFR的产生而影响治疗结果，并提示这种作用可能是由P-gp的转运蛋白功能启动的。
Treatment of animals bearing multidrug resistant (MDR) tumor cells with P-glycoprotein (P-gp) substrates could worsen host survival. It is assumed that this is due to increased tumor metastasis. To clarify the mechanism(s) underlying this observation, the MDR human breast cancer cell line, MCF-7/AdrR, and its sensitive parental line, MCF-7, was treated with various concentrations of P-gp substrate drugs (vincristine, paclitoxel, adriamycin) and a P-gp non-substrate drug (bleomycin) in serum-free media. Increased production of CD147, and matrix metalloproteinases (MMP)-2, -9 was observed only in MDR cancer cells exposed to P-gp substrates, as determined using real-time polymerase chain reaction, western blotting and zymography. Correspondingly, P-gp substrates significantly enhanced the in vitro invasion abilities of MCF-7/Adr cells. It was also found that the drug-induced promotion of CD147, and MMP-2, -9 was consistent with increased expression of epidermal growth factor receptor (EGFR) and that inhibition of either EGFR or P-gp activity could significantly interrupt the downstream effects, and so inhibit in vitro invasion abilities motivated by P-gp substrates. These results imply that treatment of MDR tumors with P-gp substrates could adversely affect therapeutic outcomes through modulating the production of CD147, MMP-2, -9, and EGFR, and suggest that this effect may be initiated by the transporter function of P-gp.