Identification of midkine as a mediator for intercellular transfer of drug resistance
Identification of midkine as a mediator for intercellular transfer of drug resistance
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DOI：
10.1038/sj.onc.1208671
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发表时间：
2005-07-21
期刊：
影响因子：
8
通讯作者：
Rebbaa, A
中科院分区：
文献类型：
--
作者：
Mirkin, BL;Clark, S;Rebbaa, A
对细胞毒性剂的抗性是其临床用于治疗人类癌症的主要限制。当一部分细胞发生分子变化，导致药物转运蛋白过度表达、药物-靶点相互作用改变或导致细胞凋亡能力降低时，肿瘤就会对化疗产生耐药性。然而，这种变化可能不足以解释为什么耐药细胞和非耐药细胞在最终成为耐药的肿瘤中的药物作用下存活下来。我们假设，在这种肿瘤中，耐药细胞和邻近的药物敏感细胞之间可能存在细胞保护关系。本研究解决了耐药细胞在其培养基中分泌能够保护敏感细胞免受药物毒性的因子的可能性。一种生存分子，中期因子，通过cDNA阵列鉴定仅在耐药细胞中表达。通过亲和色谱法获得的富含中期因子的组分对野生型药物敏感细胞中的多柔比星产生显著的细胞保护作用。此外，用中期因子基因转染这些细胞引起对阿霉素的反应降低。这种细胞保护的潜在机制似乎暗示Akt通路的激活和药物诱导的增殖停滞以及凋亡细胞死亡的抑制。这些发现为细胞间细胞保护信号的存在提供了证据，例如由中期因子介导的细胞保护信号，其源自具有获得性耐药性的细胞以保护邻近的药物敏感细胞，从而促进对化疗的耐药性的发展。
Resistance to cytotoxic agents is a major limitation for their clinical use to treat human cancers. Tumors become resistant to chemotherapy when a subset of cells undergoes molecular changes leading to overexpression of drug transport proteins, alterations in drug-target interactions or reduced ability to commit apoptosis. However, such changes may not be sufficient to explain why both resistant and nonresistant cells survive drug's action in tumors that ultimately become drug resistant. We hypothesized that, in such tumors, a cytoprotective relationship may exist between drug-resistant and neighboring drug-sensitive cells. The present study addresses the possibility that drug-resistant cells secrete in their culture medium factors able to protect sensitive cells from drug toxicity. A survival molecule, midkine, was identified by cDNA array to be expressed only in drug-resistant cells. Midkine-enriched fractions obtained by affinity chromatography exert a significant cytoprotective effect against doxorubicin in the wild-type drug-sensitive cells. Moreover, transfection of these cells with the midkine gene caused a decreased response to doxorubicin. The underlying mechanism of this cytoprotection appeared to imply activation of the Akt pathway and inhibition of drug-induced proliferation arrest as well as apoptotic cell death. These findings provide evidence for the existence of intercellular cytoprotective signals such as the one mediated by midkine, originating from cells with acquired drug resistance to protect neighboring drug-sensitive cells and thus contribute to development of resistance to chemotherapy.