Tangeretin Sensitizes SGS1-Deficient Cells by Inducing DNA Damage

Tangeretin, a polymethoxyflavone found in citrus peel, has been shown to have antiatherogenic, anti-inflammatory, and anticarcinogenic properties. However, the underlying target pathways are not fully characterized. We investigated the tangeretin sensitivity of yeast (Saccharomyces cerevisiae) mutants for DNA damage response or repair pathways. We found that tangeretin treatment significantly reduced (p sgs1Δ cells, but had no obvious effects on wild-type cells or mutants of the DNA damage checkpoint (including tel1Δ, sml1Δ mec1Δ, sml1Δ mec1Δ tel1Δ, and rad9Δ mutants). Additionally, microarray data indicated that tangeretin treatment up-regulates genes involved in nutritional processing and down-regulates genes related to RNA processing in sgs1Δ mutants. These results suggest tangeretin may sensitize SGS1-deficient cells by increasing a marker of DNA damage and by inducing G1 arrest and possibly metabolic stress. Thus, tangeretin may be suitable for chemosensitization of cancer cells lacking DSB-repair ability.川陈皮素（Tangeretin）是一种存在于柑橘果皮中的多甲氧基黄酮，已被证实具有抗动脉粥样硬化、抗炎及抗癌的生物学活性。然而其发挥作用的潜在靶点通路尚未完全阐明。本研究针对参与DNA损伤应答或修复通路的酿酒酵母（Saccharomyces cerevisiae）突变体，探究其对川陈皮素的敏感性。结果显示，川陈皮素处理可显著降低sgs1Δ突变体细胞的存活率（原文未完整提供p值相关信息），但对野生型细胞或DNA损伤检查点相关突变体（包括tel1Δ、sml1Δ、mec1Δ、sml1Δ mec1Δ tel1Δ及rad9Δ突变体）无明显影响。此外，基因芯片（microarray）数据分析表明，在sgs1Δ突变体中，川陈皮素处理可上调参与营养加工的基因，并下调与RNA加工相关的基因。上述结果提示，川陈皮素可能通过升高DNA损伤标志物水平、诱导G1期阻滞及潜在的代谢应激，使SGS1缺陷细胞对其产生敏感性。因此，川陈皮素或可用于对缺乏DNA双链断裂（DSB）修复能力的癌细胞进行化学增敏治疗。