Caveolae-Mediated Endocytosis Is Critical for Albumin Cellular Uptake and Response to Albumin-Bound Chemotherapy.
Caveolae-Mediated Endocytosis Is Critical for Albumin Cellular Uptake and Response to Albumin-Bound Chemotherapy.
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DOI：
10.1158/0008-5472.can-17-0604
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发表时间：
2017-11-01
期刊：
影响因子：
11.2
通讯作者：
Williams TM
中科院分区：
文献类型：
--
作者：
Chatterjee M;Ben-Josef E;Robb R;Vedaie M;Seum S;Thirumoorthy K;Palanichamy K;Harbrecht M;Chakravarti A;Williams TM
白蛋白结合型紫杉醇 (Nab-paclitaxel) 是紫杉醇与人白蛋白的纳米颗粒缀合物，对胰腺癌、非小细胞肺癌和乳腺癌具有疗效。然而，缺乏预测性生物标志物来识别可能从其给药中受益最多的患者。本研究通过确定 Caveolin-1 (Cav-1) 是一种基于机制的候选生物标志物来解决这一知识空白。小凹是小膜内陷，对于跨内皮白蛋白摄取很重要。 Cav-1 是小窝的主要结构成分，在上述对白蛋白结合型紫杉醇有反应的癌症中过度表达。因此，我们假设 Cav-1 可能对肿瘤中白蛋白的摄取至关重要，并可能决定肿瘤对这种药物的反应。 Cav-1 蛋白水平与白蛋白结合型紫杉醇敏感性呈正相关。 RNAi介导的Cav-1表达减弱减少了癌细胞对白蛋白和白蛋白结合型紫杉醇的摄取，并使它们对白蛋白结合型紫杉醇诱导的细胞凋亡具有抵抗力。相反，Cav-1 过表达增强了白蛋白结合型紫杉醇的敏感性。细胞培养物中白蛋白结合型紫杉醇细胞抗性的选择与 Cav-1 表达的丧失相关。在小鼠异种移植模型中，Cav-1 减弱的癌细胞表现出对白蛋白结合型紫杉醇治疗的抗肿瘤作用的抵抗力。总体而言，我们的研究结果表明 Cav-1 作为白蛋白结合型紫杉醇和其他基于白蛋白的癌症治疗药物反应的预测生物标志物。
Nab-paclitaxel, a nanoparticle conjugate of paclitaxel to human albumin, exhibits efficacy in pancreatic cancer, non-small cell lung cancer and breast cancer. However, there is a lack of predictive biomarkers to identify patients who might benefit most from its administration. This study addresses this gap in knowledge by identifying that caveolin-1 (Cav-1) is a candidate mechanism-based biomarker. Caveolae are small membrane invaginations important for trans-endothelial albumin uptake. Cav-1, the principal structural component of caveolae, is overexpressed in the cancers noted above which respond to nab-paclitaxel. Thus, we hypothesized that Cav-1 may be critical for albumin uptake in tumors and perhaps determine their response to this drug. Cav-1 protein levels correlated positively with nab-paclitaxel sensitivity. RNAi-mediated attenuation of Cav-1 expression reduced uptake of albumin and nab-paclitaxel in cancer cells and rendered them resistant to nab-paclitaxel-induced apoptosis. Conversely, Cav-1 overexpression enhanced sensitivity to nab-paclitaxel. Selection for cellular resistance to nab-paclitaxel in cell culture correlated with a loss of Cav-1 expression. In mouse xenograft models, cancer cells where Cav-1 was attenuated exhibited resistance to the antitumor effects of nab-paclitaxel therapy. Overall, our findings suggest Cav-1 as a predictive biomarker for the response to nab-paclitaxel and other albumin-based cancer therapeutic drugs.