title: Berberine Targets AP-2/hTERT, NF-κB/COX-2, HIF-1α/VEGF and Cytochrome-c/Caspase Signaling to Suppress Human Cancer Cell Growth.
abstract: Berberine (BBR), an isoquinoline derivative alkaloid isolated from Chinese herbs, has a long history of uses for the treatment of multiple diseases, including cancers. However, the precise mechanisms of actions of BBR in human lung cancer cells remain unclear. In this study, we investigated the molecular mechanisms by which BBR inhibits cell growth in human non-small-cell lung cancer (NSCLC) cells. Treatment with BBR promoted cell morphology change, inhibited cell migration, proliferation and colony formation, and induced cell apoptosis. Further molecular mechanism study showed that BBR simultaneously targeted multiple cell signaling pathways to inhibit NSCLC cell growth. Treatment with BBR inhibited AP-2α and AP-2β expression and abrogated their binding on hTERT promoters, thereby inhibiting hTERT expression. Knockdown of AP-2α and AP-2β by siRNA considerably augmented the BBR-mediated inhibition of cell growth. BBR also suppressed the nuclear translocation of p50/p65 NF-κB proteins and their binding to COX-2 promoter, causing inhibition of COX-2. BBR also downregulated HIF-1α and VEGF expression and inhibited Akt and ERK phosphorylation. Knockdown of HIF-1α by siRNA considerably augmented the BBR-mediated inhibition of cell growth. Moreover, BBR treatment triggered cytochrome-c release from mitochondrial inter-membrane space into cytosol, promoted cleavage of caspase and PARP, and affected expression of BAX and Bcl-2, thereby activating apoptotic pathway. Taken together, these results demonstrated that BBR inhibited NSCLC cell growth by simultaneously targeting AP-2/hTERT, NF-κB/COX-2, HIF-1α/VEGF, PI3K/AKT, Raf/MEK/ERK and cytochrome-c/caspase signaling pathways. Our findings provide new insights into understanding the anticancer mechanisms of BBR in human lung cancer therapy.
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Lingyi
authors.initials: L
authors.lastname: Fu
authors.forename: Wangbing
authors.initials: W
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Jingshu
authors.initials: J
authors.lastname: Wang
authors.forename: Yun
authors.initials: Y
authors.lastname: Tian
authors.forename: Dingbo
authors.initials: D
authors.lastname: Shi
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhang
authors.forename: Huijuan
authors.initials: H
authors.lastname: Qiu
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Xiao
authors.forename: Tiebang
authors.initials: T
authors.lastname: Kang
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
authors.forename: Shusen
authors.initials: S
authors.lastname: Wang
authors.forename: Wuguo
authors.initials: W
authors.lastname: Deng
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001599:Berberine / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019098:Telomerase / Q000378:metabolism; D050656:Transcription Factor AP-2 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D050656:Transcription Factor AP-2; D042461:Vascular Endothelial Growth Factor A; D001599:Berberine; D045304:Cytochromes c; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C509186:TERT protein, human; D019098:Telomerase; D020169:Caspases