Department of Environmental Health Sciences, University at Albany, State University of New York, Albany, New York; Cancer Research Center, University at Albany, Rensselaer, New York.
Mol Carcinog. 2014 Jun;53(6):458-70. doi: 10.1002/mc.21995. Epub 2013 Jan 28.
Pomegranate extract (PE) inhibits the proliferation of breast cancer cells and stimulates apoptosis in MCF-7 breast cancer cells. While PE is a potent antioxidant, the present studies were conducted to examine the mechanisms of action of PE beyond antioxidation by studying cellular and molecular mechanisms underlying breast tumorigenesis. PE inhibited cell growth by inducing cell cycle arrest in G2 /M followed by the induction of apoptosis. In contrast, antioxidants N-acetylcysteine and Trolox did not affect cell growth at doses containing equivalent antioxidant capacity as PE, suggesting that growth inhibition by PE cannot solely be attributed to its high antioxidant potential. DNA microarray analysis revealed that PE downregulated genes associated with mitosis, chromosome organization, RNA processing, DNA replication and DNA repair, and upregulated genes involved in regulation of apoptosis and cell proliferation. Both microarray and quantitative RT-PCR indicated that PE downregulated important genes involved in DNA double strand break (DSB) repair by homologous recombination (HR), such as MRE11, RAD50, NBS1, RAD51, BRCA1, BRCA2, and BRCC3. Downregulation of HR genes correlated with increased levels of their predicted microRNAs (miRNAs), miR-183 (predicted target RAD50) and miR-24 (predicted target BRCA1), suggesting that PE may regulate miRNAs involved in DNA repair processes. Further, PE treatment increased the frequency of DSBs. These data suggest that PE downregulates HR which sensitizes cells to DSBs, growth inhibition and apoptosis. Because HR represents a novel target for cancer therapy, downregulation of HR by PE may be exploited for sensitization of tumors to anticancer drugs.
石榴提取物（PE）抑制乳腺癌细胞的增殖并刺激 MCF-7 乳腺癌细胞凋亡。虽然 PE 是一种有效的抗氧化剂，但本研究通过研究乳腺癌发生的细胞和分子机制，旨在研究 PE 超越抗氧化作用的作用机制。PE 通过诱导 G2 / M 期细胞周期停滞并随后诱导细胞凋亡来抑制细胞生长。相比之下，抗氧化剂 N-乙酰半胱氨酸和 Trolox 在包含与 PE 相当的抗氧化能力的剂量下不会影响细胞生长，这表明 PE 的生长抑制不能仅仅归因于其高抗氧化潜力。DNA 微阵列分析显示，PE 下调了与有丝分裂、染色体组织、RNA 加工、DNA 复制和 DNA 修复相关的基因，并上调了与细胞凋亡和增殖调控相关的基因。微阵列和定量 RT-PCR 均表明，PE 下调了与同源重组（HR）修复的 DNA 双链断裂（DSB）相关的重要基因，如 MRE11、RAD50、NBS1、RAD51、BRCA1、BRCA2 和 BRCC3。HR 基因的下调与它们预测的 microRNAs（miRNAs）的水平升高相关，如 miR-183（预测的 RAD50 靶标）和 miR-24（预测的 BRCA1 靶标），这表明 PE 可能调节参与 DNA 修复过程的 miRNAs。此外，PE 处理增加了 DSB 的频率。这些数据表明，PE 下调 HR 会使细胞对 DSB、生长抑制和凋亡敏感。因为 HR 是癌症治疗的一个新靶点，所以 PE 下调 HR 可能被用于使肿瘤对抗癌药物敏感。
