Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, Oregon 97239, USA.
Prostate. 2010 Mar 1;70(4):433-42. doi: 10.1002/pros.21077.
Metastatic prostate cancer is either inherently resistant to chemotherapy or rapidly acquires this phenotype after chemotherapy exposure. In this study, we identified a docetaxel-induced resistance mechanism centered on CCL2.
We compared the gene expression profiles in individual human prostate cancer specimens before and after exposure to chemotherapy collected from previously untreated patients who participated in a clinical trial of preoperative chemotherapy. Subsequently, we used the gain- and loss-of-function approach in vitro to identify a potential mechanism underlying chemotherapy resistance.
Among the molecular signatures associated with treatment, several genes that regulate the inflammatory response and chemokine activity were upregulated including a significant increase in transcripts encoding the CC chemokine CCL2. Docetaxel increased CCL2 expression in prostate cancer cell lines in vitro. CCL2-specific siRNA inhibited LNCaP and LAPC4 cell proliferation and enhanced the growth inhibitory effect of low-dose docetaxel. In contrast, overexpression of CCL2 or recombinant CCL2 protein stimulated prostate cancer cell proliferation and rescued cells from docetaxel-induced cytotoxicity. This protective effect of CCL2 was associated with activation of the ERK/MAP kinase and PI3K/AKT, inhibition of docetaxel-induced Bcl2 phosphorylation at serine 70, phosphorylation of Bad, and activation of caspase-3. The addition of a PI3K/AKT inhibitor Ly294002 reversed the CCL2 protection and was additive to docetaxel-induced toxicity.
These results support a mechanism of chemotherapy resistance mediated by cellular stress responses involving the induction of CCL2 expression and suggest that inhibiting CCL2 activity could enhance therapeutic responses to taxane-based therapy.
转移性前列腺癌对化疗具有内在抗性，或者在化疗暴露后迅速获得这种表型。在这项研究中，我们确定了以 CCL2 为中心的多西紫杉醇诱导的耐药机制。
我们比较了来自未接受过治疗的患者的个体人前列腺癌标本在暴露于化疗前后的基因表达谱，这些患者参加了术前化疗的临床试验。随后，我们使用体外的增益和失能方法来鉴定潜在的化疗耐药机制。
在与治疗相关的分子特征中，有几个调节炎症反应和趋化因子活性的基因上调，包括编码 CC 趋化因子 CCL2 的转录物显著增加。多西紫杉醇在体外增加前列腺癌细胞系中的 CCL2 表达。CCL2 特异性 siRNA 抑制 LNCaP 和 LAPC4 细胞增殖，并增强低剂量多西紫杉醇的生长抑制作用。相比之下，CCL2 的过表达或重组 CCL2 蛋白刺激前列腺癌细胞增殖，并使细胞免受多西紫杉醇诱导的细胞毒性。CCL2 的这种保护作用与 ERK/MAP 激酶和 PI3K/AKT 的激活、docetaxel 诱导的 Bcl2 丝氨酸 70 磷酸化的抑制、Bad 的磷酸化以及 caspase-3 的激活有关。添加 PI3K/AKT 抑制剂 Ly294002 逆转了 CCL2 的保护作用，并与多西紫杉醇诱导的毒性相加。
这些结果支持了一种化疗耐药机制，该机制涉及细胞应激反应，包括 CCL2 表达的诱导，并表明抑制 CCL2 活性可以增强基于紫杉烷的治疗的治疗反应。
