Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
Br J Nutr. 2011 Dec;106(12):1779-91. doi: 10.1017/S0007114511002315. Epub 2011 Jun 23.
Dietary isothiocyanates have been shown to possess anti-tumour activity, inhibiting several types of cultured human cancer cell growth. However, there are limited studies on their effects on cancer cell metastasis. Our previous study showed that benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC) suppressed human lung cancer cell metastasis potential. In the present study, we found BITC (7·5 and 10 μm) and PEITC (12·5 and 20 μm) induced highly metastatic human non-small cell lung cancer L9981 cell apoptosis in a dose-dependent manner. Caspase-3 was activated. They also caused cell cycle arrest at the G2/M phase, via modulation of cyclin B1 expression. The mitogen-activated protein kinase (MAPK) signalling pathway was involved. c-Jun N-terminal kinase, extracellular signal-regulated protein kinase 1/2 and p38 were activated in a dose-dependent manner; activator protein 1 (AP-1) transcriptional activation and cyclin D1 expression were repressed. Apoptosis and MAPK activation were abrogated by anti-oxidant N-acetyl cysteine (NAC), suggesting that cell death signalling was triggered by oxidative stress. Further microarray analysis evaluated the potential targeted genes related to apoptosis and the cell cycle. Our studies suggested that BITC and PEITC suppressed the metastasis potential of highly metastatic lung cancer cells by inducing apoptosis and cell cycle arrest, via targeting the MAPK/AP-1 pathway. This may provide a novel approach for metastasis therapy of lung cancer by dietary isothiocyanates and possibly other types of cancer.
膳食异硫氰酸盐已被证明具有抗肿瘤活性，能抑制多种培养的人类癌细胞生长。然而，关于其对癌细胞转移的影响的研究有限。我们之前的研究表明，苄基异硫氰酸酯（BITC）和苯乙基异硫氰酸酯（PEITC）抑制了人类肺癌细胞的转移潜能。在本研究中，我们发现 BITC（7.5 和 10μm）和 PEITC（12.5 和 20μm）以剂量依赖的方式诱导高转移性人非小细胞肺癌 L9981 细胞凋亡。半胱天冬酶-3 被激活。它们还通过调节细胞周期蛋白 B1 的表达使细胞周期停滞在 G2/M 期。丝裂原活化蛋白激酶（MAPK）信号通路参与其中。c-Jun N-末端激酶、细胞外信号调节蛋白激酶 1/2 和 p38 被激活，呈剂量依赖性；激活蛋白 1（AP-1）转录激活和细胞周期蛋白 D1 的表达受到抑制。抗氧化剂 N-乙酰半胱氨酸（NAC）阻断了细胞凋亡和 MAPK 激活，表明细胞死亡信号是由氧化应激引发的。进一步的基因芯片分析评估了与细胞凋亡和细胞周期相关的潜在靶向基因。我们的研究表明，BITC 和 PEITC 通过诱导细胞凋亡和细胞周期停滞，抑制高转移性肺癌细胞的转移潜能，作用靶点是 MAPK/AP-1 通路。这可能为通过膳食异硫氰酸盐和其他类型的癌症来治疗肺癌转移提供一种新的方法。
