Pulmonary and Critical Care Section, New Mexico VA Health Care System, Albuquerque, NM 87108, USA.
Cancer Prev Res (Phila). 2010 Sep;3(9):1132-40. doi: 10.1158/1940-6207.CAPR-09-0264. Epub 2010 Jul 28.
Emerging preclinical data suggests that tea possess anticarcinogenic and antimutagenic properties. We therefore hypothesize that white tea extract (WTE) is capable of favorably modulating apoptosis, a mechanism associated with lung tumorigenesis. We examined the effects of physiologically relevant doses of WTE on the induction of apoptosis in non-small cell lung cancer cell lines A549 (adenocarcinoma) and H520 (squamous cell carcinoma) cells. We further characterized the molecular mechanisms responsible for WTE-induced apoptosis, including the induction of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and the 15-lipoxygenase (15-LOX) signaling pathways. We found that WTE was effective in inducing apoptosis in both A549 and H520 cells, and inhibition of PPAR-gamma with GW9662 partially reversed WTE-induced apoptosis. We further show that WTE increased PPAR-gamma activation and mRNA expression, concomitantly increased 15(S)-hydroxy-eicosatetraenoic acid release, and upregulated 15-LOX-1 and 15-LOX-2 mRNA expression by A549 cells. Inhibition of 15-LOX with nordihydroguaiaretic acid (NGDA), as well as caffeic acid, abrogated WTE-induced PPAR-gamma activation and upregulation of PPAR-gamma mRNA expression in A549 cells. WTE also induced cyclin-dependent kinase inhibitor 1A mRNA expression and activated caspase-3. Inhibition of caspase-3 abrogated WTE-induced apoptosis. Our findings indicate that WTE is capable of inducing apoptosis in non-small cell lung cancer cell lines. The induction of apoptosis seems to be mediated, in part, through the upregulation of the PPAR-gamma and 15-LOX signaling pathways, with enhanced activation of caspase-3. Our findings support the future investigation of WTE as an antineoplastic and chemopreventive agent for lung cancer.
新兴的临床前数据表明，茶具有抗癌和抗突变的特性。因此，我们假设白茶提取物（WTE）能够有效地调节细胞凋亡，而细胞凋亡是与肺癌发生相关的一种机制。我们研究了生理相关剂量的 WTE 对非小细胞肺癌细胞系 A549（腺癌）和 H520（鳞状细胞癌）细胞凋亡诱导的影响。我们进一步表征了 WTE 诱导细胞凋亡的分子机制，包括过氧化物酶体增殖物激活受体-γ（PPAR-γ）和 15-脂氧合酶（15-LOX）信号通路的诱导。我们发现 WTE 能有效诱导 A549 和 H520 细胞凋亡，用 GW9662 抑制 PPAR-γ 部分逆转了 WTE 诱导的细胞凋亡。我们进一步表明，WTE 增加了 PPAR-γ 的激活和 mRNA 表达，同时增加了 A549 细胞中 15(S)-羟基二十碳四烯酸的释放，并上调了 15-LOX-1 和 15-LOX-2 mRNA 的表达。用 nordihydroguaiaretic acid (NGDA) 抑制 15-LOX 以及咖啡酸，可阻断 WTE 诱导的 A549 细胞中 PPAR-γ 的激活和 PPAR-γ mRNA 的上调。WTE 还诱导细胞周期蛋白依赖性激酶抑制剂 1A mRNA 的表达并激活半胱氨酸天冬氨酸蛋白酶-3。抑制半胱氨酸天冬氨酸蛋白酶-3 可阻断 WTE 诱导的细胞凋亡。我们的研究结果表明，WTE 能够诱导非小细胞肺癌细胞系凋亡。凋亡的诱导似乎部分通过上调 PPAR-γ 和 15-LOX 信号通路，增强半胱氨酸天冬氨酸蛋白酶-3 的激活来介导。我们的研究结果支持未来对 WTE 作为肺癌的抗肿瘤和化学预防剂的研究。
