Cytoplasmic GPER translocation in cancer-associated fibroblasts mediates cAMP/PKA/CREB/glycolytic axis to confer tumor cells with multidrug resistance
Cytoplasmic GPER translocation in cancer-associated fibroblasts mediates cAMP/PKA/CREB/glycolytic axis to confer tumor cells with multidrug resistance
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癌症相关成纤维细胞中的细胞质 GPER 易位介导 cAMP/PKA/CREB/糖酵解轴，赋予肿瘤细胞多药耐药性
DOI：
10.1038/onc.2016.370
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发表时间：
2017-04-13
期刊：
影响因子：
8
通讯作者：
Liu, M.
中科院分区：
文献类型：
--
作者：
Yu, T.;Yang, G.;Liu, M.
多药耐药是临床上一个具有挑战性的问题。越来越多的证据表明，G蛋白偶联雌激素受体（GPER）是雌激素受体（ER）阳性和阴性乳腺癌多药耐药发展的新介质，肿瘤微环境中的癌症相关成纤维细胞（CAFs）可能是促进肿瘤细胞耐药性的新试剂。然而，CAFs胞浆GPER在肿瘤治疗中的作用尚不清楚。我们首次发现乳腺肿瘤细胞激活的PI 3 K/AKT（磷酸肌醇3-激酶/AKT）信号通路以CRM 1依赖的方式诱导CAFs的胞质GPER易位，并导致新的雌激素/GPER/cAMP/PKA/CREB信号轴激活，从而触发CAFs的有氧糖酵解开关。糖酵解CAF将额外的丙酮酸和乳酸供给肿瘤细胞以增强线粒体活性，并且这种能量在分解代谢CAF和合成代谢癌细胞之间的“宿主-寄生虫关系”中代谢偶联，赋予肿瘤细胞对几种常规临床治疗包括内分泌治疗（他莫昔芬）、Her-2靶向治疗（赫赛汀）和化疗（表阿霉素）的多重耐药性。此外，来自18 F-氟脱氧葡萄糖正电子发射断层扫描/计算机断层扫描的临床数据进一步呈现了间质成纤维细胞的GPER/cAMP/PKA/CREB通路与肿瘤代谢活性和临床治疗之间的强关联，这表明靶向CAF中的细胞质GPER可以挽救乳腺癌患者的药物敏感性。因此，我们的数据从肿瘤能量代谢重编程的角度定义了对基质GPER介导的多药耐药的新见解，并为CAFs作为临床治疗的有希望的靶点提供了理论基础。
Multiple drug resistance is a challenging issue in the clinic. There is growing evidence that the G-protein-coupled estrogen receptor (GPER) is a novel mediator in the development of multidrug resistance in both estrogen receptor (ER)-positive and-negative breast cancers, and that cancer-associated fibroblasts (CAFs) in the tumor microenvironment may be a new agent that promotes drug resistance in tumor cells. However, the role of cytoplasmic GPER of CAFs on tumor therapy remains unclear. Here we first show that the breast tumor cell-activated PI3K/AKT (phosphoinositide 3-kinase/AKT) signaling pathway induces the cytoplasmic GPER translocation of CAFs in a CRM1-dependent pattern, and leads to the activation of a novel estrogen/GPER/cAMP/PKA/CREB signaling axis that triggers the aerobic glycolysis switch in CAFs. The glycolytic CAFs feed the extra pyruvate and lactate to tumor cells for augmentation of mitochondrial activity, and this energy metabolically coupled in a ‘host–parasite relationship’between catabolic CAFs and anabolic cancer cells confers the tumor cells with multiple drug resistance to several conventional clinical treatments including endocrine therapy (tamoxifen), Her-2-targeted therapy (herceptin) and chemotherapy (epirubicin). Moreover, the clinical data from 18 F-fluorodeoxyglucose positron emission tomography/computed tomography further present a strong association between the GPER/cAMP/PKA/CREB pathway of stromal fibroblasts with tumor metabolic activity and clinical treatment, suggesting that targeting cytoplasmic GPER in CAFs may rescue the drug sensitivity in patients with breast cancer. Thus, our data define novel insights into the stromal GPER-mediated multiple drug resistance from the point of reprogramming of tumor energy metabolism and provide the rationale for CAFs as a promising target for clinical therapy.