title: Mitogen-activated protein kinase mediates the apoptosis of highly metastatic human non-small cell lung cancer cells induced by isothiocyanates.
abstract: 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.
authors: Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
authors: Huiqin
authors: H
authors: Yan
authors: Yu
authors: Y
authors: Zhu
authors: Boning
authors: B
authors: Liu
authors: Heng
authors: H
authors: Wu
authors: Yongwen
authors: Y
authors: Li
authors: Xiang
authors: X
authors: Wu
authors: Qinghua
authors: Q
authors: Zhou
authors: Ke
authors: K
authors: Xu
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D056744:Cyclin B1 / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology*; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000517:prevention & control; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D000975:Antioxidants; C534699:CCNB1 protein, human; D056744:Cyclin B1; D017879:Isothiocyanates; D018808:Transcription Factor AP-1; C058305:phenethyl isothiocyanate; C031403:benzyl isothiocyanate; D000111:Acetylcysteine