Sung Bokyung, Jhurani Sonia, Ahn Kwang Seok, Mastuo Yoichi, Yi Tingfang, Guha Sushovan, Liu Mingyao, Aggarwal Bharat B
Department of Experimental Therapeutics, Cytokine Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cancer Res. 2008 Nov 1;68(21):8938-44. doi: 10.1158/0008-5472.CAN-08-2155.
CXC chemokine receptor 4 (CXCR4), initially linked with leukocyte trafficking, is now known to be expressed in various tumors including breast, ovary, prostate, gastrointestinal, head and neck, bladder, brain, and melanoma. This receptor mediates homing of tumor cells to specific organs that express the ligand CXCL12 for this receptor. Thus, agents that can down-regulate CXCR4 expression have potential against cancer metastasis. In this study, we report the identification of zerumbone, a component of subtropical ginger (Zingiber zerumbet), as a regulator of CXCR4 expression. This sesquiterpene down-regulated the expression of CXCR4 on HER2-overexpressing breast cancer cells in a dose- and time-dependent manner. The decrease in CXCR4 by zerumbone was found to be not cell type specific as its expression was abrogated in leukemic, skin, kidney, lung, and pancreatic cancer cell lines. The down-regulation of CXCR4 was not due to proteolytic degradation but rather to transcriptional regulation, as indicated by down-regulation of mRNA expression, inhibition of nuclear factor-kappaB activity, and suppression of chromatin immunoprecipitation activity. Suppression of CXCR4 expression by zerumbone correlated with the inhibition of CXCL12-induced invasion of both breast and pancreatic cancer cells. An analogue of zerumbone, alpha-humulene, which lacks the carbonyl group, was found to be inactive in inducing CXCR4 down-regulation. Overall, our results show that zerumbone is a novel inhibitor of CXCR4 expression and thus has a potential in the suppression of cancer metastasis.
CXC趋化因子受体4（CXCR4）最初与白细胞运输有关，现在已知它在包括乳腺癌、卵巢癌、前列腺癌、胃肠道癌、头颈癌、膀胱癌、脑癌和黑色素瘤在内的多种肿瘤中表达。该受体介导肿瘤细胞归巢至表达其配体CXCL12的特定器官。因此，能够下调CXCR4表达的药物具有对抗癌症转移的潜力。在本研究中，我们报告了亚热带姜（红球姜）的一种成分——姜酮，可作为CXCR4表达的调节剂。这种倍半萜以剂量和时间依赖性方式下调HER2过表达乳腺癌细胞上CXCR4的表达。发现姜酮对CXCR4的降低并非细胞类型特异性的，因为其在白血病、皮肤、肾、肺和胰腺癌细胞系中的表达被消除。CXCR4的下调不是由于蛋白水解降解，而是由于转录调控，这可通过mRNA表达下调、核因子-κB活性抑制和染色质免疫沉淀活性抑制来表明。姜酮对CXCR4表达的抑制与CXCL12诱导的乳腺癌和胰腺癌细胞侵袭的抑制相关。姜酮的类似物α-葎草烯（缺乏羰基）在诱导CXCR4下调方面无活性。总体而言，我们的结果表明姜酮是CXCR4表达的新型抑制剂，因此在抑制癌症转移方面具有潜力。
