title: Involvement of Nrf2-mediated upregulation of heme oxygenase-1 in mollugin-induced growth inhibition and apoptosis in human oral cancer cells.
abstract: Although previous studies have shown that mollugin, a bioactive phytochemical isolated from Rubia cordifolia L. (Rubiaceae), exhibits antitumor effects, its biological activity in oral cancer has not been reported. We thus investigated the effects and putative mechanism of apoptosis induced by mollugin in human oral squamous cell carcinoma cells (OSCCs). Results show that mollugin induces cell death in a dose-dependent manner in primary and metastatic OSCCs. Mollugin-induced cell death involved apoptosis, characterized by the appearance of nuclear shrinkage, flow cytometric analysis of sub-G1 phase arrest, and annexin V-FITC and propidium iodide staining. Western blot analysis and RT-PCR revealed that mollugin suppressed activation of NF- κ B and NF- κ B-dependent gene products involved in antiapoptosis (Bcl-2 and Bcl-xl), invasion (MMP-9 and ICAM-1), and angiogenesis (FGF-2 and VEGF). Furthermore, mollugin induced the activation of p38, ERK, and JNK and the expression of heme oxygenase-1 (HO-1) and nuclear factor E2-related factor 2 (Nrf2). Mollugin-induced growth inhibition and apoptosis of HO-1 were reversed by an HO-1 inhibitor and Nrf2 siRNA. Collectively, this is the first report to demonstrate the effectiveness of mollugin as a candidate for a chemotherapeutic agent in OSCCs via the upregulation of the HO-1 and Nrf2 pathways and the downregulation of NF- κ B.
authors.affiliation: Department of Maxillofacial Tissue Regeneration and Research Center for Tooth & Periodontal Regeneration, School of Dentistry, Kyung Hee University, 1 Heogi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Young-Man
authors.initials: YM
authors.lastname: Lee
authors.forename: Q-Schick
authors.initials: QS
authors.lastname: Auh
authors.forename: Deok-Won
authors.initials: DW
authors.lastname: Lee
authors.forename: Jun-Yeol
authors.initials: JY
authors.lastname: Kim
authors.forename: Ha-Jin
authors.initials: HJ
authors.lastname: Jung
authors.forename: Seung-Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Eun-Cheol
authors.initials: EC
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011714:Pyrans / Q000494:pharmacology* / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D011714:Pyrans; D034741:RNA, Small Interfering; C046245:rubimaillin; D051547:Heme Oxygenase-1; D020928:Mitogen-Activated Protein Kinases