The Hedgehog Receptor Patched Functions in Multidrug Transport and Chemotherapy Resistance
The Hedgehog Receptor Patched Functions in Multidrug Transport and Chemotherapy Resistance
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DOI：
10.1158/1541-7786.mcr-11-0578
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发表时间：
2012-11-01
影响因子：
5.2
通讯作者：
Mus-Veteau, Isabelle
中科院分区：
文献类型：
--
作者：
Bidet, Michel;Tomico, Amandine;Mus-Veteau, Isabelle
大多数抗癌药物不能根除肿瘤，导致耐药性和疾病复发的发展。Hedgehog信号在胚胎发育过程中起着至关重要的作用，但也参与癌症的发展，进展和转移。Hedgehog受体Patched（Ptc）是一种在许多癌细胞中过表达的Hedgehog信号靶基因。在这里，我们展示了Ptc和化疗耐药性之间的联系，并为Ptc功能提供了新的见解。Ptc在与其配体Hedgehog相互作用后或在用Hedgehog信号传导拮抗剂环巴胺处理细胞后从质膜上清除。在这两种情况下，细胞与阿霉素（一种用于复发性癌症临床管理的化疗剂）孵育后，我们观察到阿霉素从Hedgehog反应成纤维细胞流出的抑制，以及已知表达异常水平的Hedgehog信号传导组分的两种不同癌细胞系中阿霉素积累的增加。利用异源表达系统，我们严格地表明，表达的人Ptc赋予耐生长抑制的几种药物，化疗药物，如阿霉素，甲氨蝶呤，替莫唑胺，5-氟尿嘧啶。对阿霉素的抗性与Ptc功能相关，如使用来自Gorlin综合征患者的突变所示，其中Ptc介导的对Hedgehog信号传导的作用丧失。我们的研究结果表明，Ptc参与药物外排和多药耐药，并建议Ptc有助于肿瘤细胞的化疗耐药性。Mol Cancer Res; 10（11）; 1496-508. (C)2012年AACR。
Most anticancer drugs fail to eradicate tumors, leading to the development of drug resistance and disease recurrence. The Hedgehog signaling plays a crucial role during embryonic development, but is also involved in cancer development, progression, and metastasis. The Hedgehog receptor Patched (Ptc) is a Hedgehog signaling target gene that is overexpressed in many cancer cells. Here, we show a link between Ptc and resistance to chemotherapy, and provide new insight into Ptc function. Ptc is cleared from the plasma membrane upon interaction with its ligand Hedgehog, or upon treatment of cells with the Hedgehog signaling antagonist cyclopamine. In both cases, after incubation of cells with doxorubicin, a chemotherapeutic agent that is used for the clinical management of recurrent cancers, we observed an inhibition of the efflux of doxorubicin from Hedgehog-responding fibroblasts, and an increase of doxorubicin accumulation in two different cancer cell lines that are known to express aberrant levels of Hedgehog signaling components. Using heterologous expression system, we stringently showed that the expression of human Ptc conferred resistance to growth inhibition by several drugs from which chemotherapeutic agents such as doxorubicin, methotrexate, temozolomide, and 5-fluorouracil. Resistance to doxorubicin correlated with Ptc function, as shown using mutations from Gorlin's syndrome patients in which the Ptc-mediated effect on Hedgehog signaling is lost. Our results show that Ptc is involved in drug efflux and multidrug resistance, and suggest that Ptc contributes to chemotherapy resistance of cancer cells. Mol Cancer Res; 10(11); 1496-508. (C) 2012 AACR.