期刊
PROTEOMICS
卷 15, 期 19, 页码 3296-3309出版社
WILEY
DOI: 10.1002/pmic.201400568
关键词
-Bisabolene; Cell biology; Histone deacetylase; Oral squamous cell carcinoma; Phosphoproteomics; P53 acetylation
资金
- National Science Council of Taiwan [NSC102-2320-B-039-044-MY3]
- China Medical University [CMU102-ASIA-15, CMU103-ASIA-07]
-Bisabolene, one of main components in cardamom, showed potent in vitro and in vivo anti-proliferative activities against human oral squamous cell carcinoma (OSCC). -Bisabolene activated caspases-3/9 and decreased mitochondrial memebrane potential, leading to apoptosis of OSCC cell lines (Ca9-22 and SAS), but not normal oral fibroblast cells. Phosphoproteome profiling of OSCC cells treated with -bisabolene was identified using TiO2-PDMS plate and LC-MS/MS, then confirmed using Western blotting and real-time RT-PCR assays. Phosphoproteome profiling revealed that -bisabolene increased the phosphorylation of ERK1/2, protein phosphatases 1 (PP1), and p53, as well as decreased the phosphorylation of histone deacetylase 2 (HDAC2) in the process of apoptosis induction. Protein-protein interaction network analysis proposed the involvement of PP1-HDAC2-p53 and ERK1/2-p53 pathways in -bisabolene-induced apoptosis. Subsequent assays indicated -bisabolene eliciting p53 acetylation that enhanced the expression of p53-regulated apoptotic genes. PP1 inhibitor-2 restored the status of HDAC2 phosphorylation, reducing p53 acetylation and PUMA mRNA expression in -bisabolene-treated Ca9-22 and SAS cells. Meanwhile, MEK and ERK inhibitors significantly decreased -bisabolene-induced PUMA expression in both cancer cell lines. Notably, the results ascertained the involvement of PP1-HDAC2-p53 and ERK1/2-p53 pathways in mitochondria-mediated apoptosis of -bisabolene-treated cells. This study demonstrated -bisabolene displaying potent anti-proliferative and apoptosis-inducing activities against OSCC in vitro and in vivo, elucidating molecular mechanisms of -bisabolene-induced apoptosis. The novel insight could be useful for developing anti-cancer drugs.
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