TLR4 is a novel determinant of the response to paclitaxel in breast cancer.
TLR4 is a novel determinant of the response to paclitaxel in breast cancer.
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DOI：
10.1158/1535-7163.mct-12-1019
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发表时间：
2013-08
影响因子：
5.7
通讯作者：
Ran S
中科院分区：
文献类型：
--
作者：
Rajput S;Volk-Draper LD;Ran S
Toll样受体-4（TLR 4）在人类肿瘤中的过表达通常与化疗耐药性和转移相关。我们发现，TLR 4在大多数临床乳腺癌（BC）样本和68%的检查BC系中过表达。TLR 4被脂多糖（LPS）和其他配体（包括广泛使用的药物紫杉醇（PXL））激活。LPS经常用于显示TLR 4的肿瘤促进作用，尽管这种细菌组分不太可能在BC环境中发现。我们推断，TLR 4的PXL依赖性激活与BC化疗耐药性更相关，这可能是通过NF-κB途径的激活介导的，导致促存活基因的上调。为了验证这一假设，我们将TLR 4表达与两个修饰的BC系中对PXL的抗性相关联，所述BC系具有耗尽或过表达的TLR 4蛋白。在天然过表达的MDA-MB-231细胞中TLR 4的消耗下调促存活基因，伴随着体外对PXL的IC 50降低2-3倍和体内复发率降低6倍。相反，在阴性细胞系HCC 1806中TLR 4过表达显著增加了炎性和促存活基因的表达沿着体外对PXL的IC 50增加了3倍，并增强了体内肿瘤对PXL治疗的抗性。重要的是，两种肿瘤模型均显示许多PXL上调的炎性细胞因子与其受体共诱导，表明该疗法诱导自分泌肿瘤促进环。总的来说，这些结果表明紫杉醇不仅杀死肿瘤细胞，而且通过激活TLR 4途径增强其存活。这些发现表明，阻断TLR 4可以显著改善对PXL治疗的反应。
Overexpression of Toll-like Receptor-4 (TLR4) in human tumors often correlates with chemoresistance and metastasis. We found that TLR4 is overexpressed in the majority of clinical breast cancer (BC) samples and in 68% of the examined BC lines. TLR4 is activated by lipopolysaccharide (LPS) and other ligands including the widely-used drug paclitaxel (PXL). LPS is frequently used to show a tumor-promoting role of TLR4 although this bacterial component is unlikely to be found in BC environment. We reasoned that PXL-dependent activation of TLR4 is more relevant to BC chemoresistance that could be mediated by activation of the NF-κB pathway leading to upregulation of pro-survival genes. To test this hypothesis, we correlated TLR4 expression with resistance to PXL in two modified BC lines with either depleted or overexpressed TLR4 protein. Depletion of TLR4 in naturally overexpressing MDA-MB-231 cells downregulated pro-survival genes concomitant with 2–3 fold reduced IC50 to PXL in vitro and a 6-fold decrease in recurrence rate in vivo. Conversely, TLR4 overexpression in a negative cell line HCC1806 significantly increased expression of inflammatory and pro-survival genes along with a 3-fold increase of IC50 to PXL in vitro and enhanced tumor resistance to PXL therapy in vivo. Importantly, both tumor models showed that many PXL-upregulated inflammatory cytokines were co-induced with their receptors suggesting that this therapy induces autocrine tumor-promoting loops. Collectively, these results demonstrate that paclitaxel not only kills tumor cells but also enhances their survival by activating TLR4 pathway. These findings suggest that blocking TLR4 could significantly improve response to PXL therapy.