Ullmannova Veronika, Popescu Nicholas C
Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, 37 Convent Drive, MSC 4264, Bethesda, MD 20892-4255, USA.
Cancer Detect Prev. 2007;31(2):110-8. doi: 10.1016/j.cdp.2007.02.005. Epub 2007 Apr 6.
Dietary flavone was previously shown to increase the expression of deleted in liver cancer-1 gene (DLC-1) in HT-29 colon carcinoma cell line [Herzog A, Kindermann B, Doring F, Daniel H, Wenzel U. Pleiotropic molecular effects of the pro-apoptotic dietary constituent flavone in human colon cancer cells identified by protein and mRNA expression profiling. Proteomics 2004;4:2455-64]. DLC-1 that encodes a Rho GTPase-activating protein, functions as a tumor suppressor gene and is frequently inactivated or down-regulated in several common cancers. Restoration of DLC-1 expression suppresses in vitro tumor cells proliferation and tumorigenicity in vivo.
Here, the effect of flavone was examined in several DLC-1-deficient cell lines derived from different types human cancer using assays for cell proliferation, gene expression and transfer.
We show that exposure to 150 microM flavone increased DLC1 expression in breast but not in liver or prostate carcinoma cells or a nonmalignant breast epithelial cell line. Flavone restored the expression of DLC1 in the breast carcinoma cell lines MDA-MB-468, MDA-MB-361, and BT20 as well as in the colon carcinoma cell line HT-29 all of which are DLC-1-negative due to promoter hypermethylation. We further show that flavone inhibited cell proliferation, induced cell cycle arrest at G(2)-M, increased p21(Waf1) gene expression, and caused apoptosis. Microarray analysis of these aggressive and metastatic breast carcinoma cells revealed 29 flavone-responsive genes, among which the DNA damage-inducible GADD genes were up-regulated and the proto-oncogene STMN1 and IGFBP3 were down-regulated.
Flavone-mediated alterations of genes that regulate tumor cell proliferation, cell cycle, and apoptosis contribute to chemopreventive and antitumoral effects of flavone. Alone or in combination with demethylating agents, flavone may be an effective adjunct to chemotherapy in preventing breast cancer metastasis.
先前的研究表明，膳食黄酮可增加HT-29结肠癌细胞系中肝癌缺失基因1（DLC-1）的表达[Herzog A, Kindermann B, Doring F, Daniel H, Wenzel U. 通过蛋白质和mRNA表达谱分析确定促凋亡膳食成分黄酮对人结肠癌细胞的多效分子作用。蛋白质组学2004;4:2455 - 64]。DLC-1编码一种Rho GTP酶激活蛋白，作为一种肿瘤抑制基因，在几种常见癌症中经常失活或下调。恢复DLC-1表达可抑制体外肿瘤细胞增殖和体内肿瘤发生能力。
在此，使用细胞增殖、基因表达和转移检测方法，研究黄酮在源自不同类型人类癌症的几种DLC-1缺陷细胞系中的作用。
我们发现，暴露于150微摩尔的黄酮可增加乳腺癌细胞中DLC1的表达，但在肝癌、前列腺癌细胞或非恶性乳腺上皮细胞系中则无此作用。黄酮可恢复乳腺癌细胞系MDA-MB-468、MDA-MB-361和BT20以及结肠癌细胞系HT-29中DLC1的表达，这些细胞系由于启动子高甲基化均为DLC-1阴性。我们进一步表明，黄酮可抑制细胞增殖，诱导细胞周期停滞在G(2)-M期，增加p21(Waf1)基因表达，并导致细胞凋亡。对这些侵袭性和转移性乳腺癌细胞进行微阵列分析，发现了29个黄酮反应基因，其中DNA损伤诱导的GADD基因上调，原癌基因STMN1和IGFBP3下调。
黄酮介导的调节肿瘤细胞增殖、细胞周期和凋亡的基因改变，有助于黄酮的化学预防和抗肿瘤作用。单独或与去甲基化剂联合使用，黄酮可能是预防乳腺癌转移化疗的有效辅助药物。
