title: Extracellular signal-regulated kinase signaling-mediated induction and interaction of FOXO3a and p53 contribute to the inhibition of nasopharyngeal carcinoma cell growth by curcumin.
abstract: Curcumin, one of the main bioactive components extracted from a traditional Chinese medicinal herb, exhibits potent anticancer activity against many types of cancer cells including nasopharyngeal carcinoma (NPC). However, the detailed molecular mechanism underlying this is not clearly understood. In this study, we showed that curcumin significantly inhibited the growth of NPC cells in a dose- and time-dependent manner as determined by MTT assays, while increasing apoptosis was also observed as measured by flow cytometry for the FITC-Annexin V and propidium iodide (PI) label and Hoechst 33258 staining. To further explore the potential mechanism, we showed that curcumin increased the phosphorylation of ERK1/2 but not p38 MAPK in a time-dependent manner, and induced protein expression of the tumor suppressors FOXO3a and p53 in a dose‑dependent manner, which were not observed in the presence of PD98059, an inhibitor of ERK1/2. Furthermore, silencing of FOXO3a and p53 genes by siRNAs overcame the inhibitory effect of curcumin on cell proliferation. Silencing or blockade of p53 using siRNA or chemical inhibitor abrogated the effect of curcumin on expression of FOXO3a protein; silencing or overexpression of FOXO3a had no further effect on curcumin-induced p53 protein expression. Furthermore, blockade of ERK1/2 and exogenous expression of FOXO3a restored the effect of curcumin on growth of cells. Together, our studies show that curcumin inhibits growth and induces apoptosis of NPC cells through ERK1/2-mediated increase in the protein expression and interaction of p53 and FOXO3a. p53 is upstream of FOXO3a, which form a regulatory loop that mediates the effect of curcumin. This study unveils a new mechanism by which curcumin inhibits the proliferation and induces apoptosis of human NPC cells.
authors.affiliation: Laboratory of Tumor Molecular Biology and Targeted Therapies of Chinese Medicine, University of Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, P.R. China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Laboratory of Tumor Molecular Biology and Targeted Therapies of Chinese Medicine, University of Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, P.R. China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Laboratory of Tumor Molecular Biology and Targeted Therapies of Chinese Medicine, University of Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, P.R. China.
authors.forename: Shunyu
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Laboratory of Tumor Molecular Biology and Targeted Therapies of Chinese Medicine, University of Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Laboratory of Tumor Molecular Biology and Targeted Therapies of Chinese Medicine, University of Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Laboratory of Tumor Molecular Biology and Targeted Therapies of Chinese Medicine, University of Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, P.R. China.
authors.forename: Ge
authors.initials: G
authors.lastname: Tang
authors.affiliation: Laboratory of Tumor Molecular Biology and Targeted Therapies of Chinese Medicine, University of Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, P.R. China.
authors.forename: Swei Sunny
authors.initials: SS
authors.lastname: Hahn
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000008:administration & dosage* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C499517:FOXO3 protein, human; D005419:Flavonoids; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003474:Curcumin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one