Hurnanen D, Chan H M, Kubow S
School of Dietetics and Human Nutrition and Center for Indigenous Peoples' Nutrition and Environment, Macdonald Campus of McGill University, Quebec, Canada.
J Pharmacol Exp Ther. 1997 Dec;283(3):1520-8.
The treatment of breast cancer by retinoic acid (RA) may be mediated by lipid peroxidation. Expression of metallothionein (MT) in cancer cells, however, can protect against lipid peroxidation by scavenging hydroxyl radicals. In this study, a two-by-six factorial design was used to investigate the interactive effects of all-trans-RA and zinc (Zn)-induced MT on the growth of two human breast cancer cell lines differing in basal expression of MT and estrogen receptors; MCF7 cells express estrogen receptor, BT-20 cells do not. Cells were treated with Zn to induce MT and then treated with six RA concentrations. Cell proliferation, lipid peroxidation, MT protein, MT mRNA and glutathione concentrations were measured. BT-20 cells expressed higher constitutive MT concentrations than MCF7 cells. MT was significantly increased by Zn treatment in BT-20 cells but not in MCF7 cells. Low RA concentrations stimulated growth proliferation but higher concentrations inhibited cell proliferation. Elevated RA concentrations increased lipid peroxidation as measured by thiobarbituric acid reactive substances. There was a significant negative correlation between lipid peroxidation and cell proliferation. Growth inhibition and lipid peroxidation were reduced by Zn pretreatment in BT-20 cells but not in MCF7 cells. RA increased MT levels in both cell lines, which suggests that RA may generate free radicals which will induce MT mRNA expression. Glutathione did not appear to be a significant factor. Therefore, induction of MT by Zn may modulate the growth inhibitory effects of RA in human breast cancer cells. One mechanism of growth inhibition may be through increased lipid peroxidation. Induction of MT by RA may be one explanation for acquired RA resistance in cancer.
视黄酸（RA）对乳腺癌的治疗作用可能是通过脂质过氧化介导的。然而，癌细胞中金属硫蛋白（MT）的表达可通过清除羟自由基来防止脂质过氧化。在本研究中，采用二乘六析因设计来研究全反式视黄酸和锌（Zn）诱导的MT对两种人乳腺癌细胞系生长的交互作用，这两种细胞系在MT和雌激素受体的基础表达上存在差异；MCF7细胞表达雌激素受体，BT - 20细胞不表达。用锌处理细胞以诱导MT表达，然后用六种视黄酸浓度进行处理。测量细胞增殖、脂质过氧化、MT蛋白、MT mRNA和谷胱甘肽浓度。BT - 20细胞的组成型MT浓度高于MCF7细胞。锌处理使BT - 20细胞中的MT显著增加，但MCF7细胞中未增加。低浓度视黄酸刺激生长增殖，而高浓度则抑制细胞增殖。通过硫代巴比妥酸反应性物质测量，升高的视黄酸浓度增加了脂质过氧化。脂质过氧化与细胞增殖之间存在显著负相关。锌预处理可降低BT - 20细胞中的生长抑制和脂质过氧化，但MCF7细胞中未降低。视黄酸增加了两种细胞系中的MT水平，这表明视黄酸可能产生自由基，从而诱导MT mRNA表达。谷胱甘肽似乎不是一个重要因素。因此，锌诱导的MT可能调节视黄酸对人乳腺癌细胞的生长抑制作用。生长抑制的一种机制可能是通过增加脂质过氧化。视黄酸诱导MT可能是癌症中获得性视黄酸耐药的一种解释。
