Berberine Targets AP-2/hTERT, NF-κB/COX-2, HIF-1α/VEGF and Cytochrome-c/Caspase Signaling to Suppress Human Cancer Cell Growth

• Published in: PloS one Vol. 8; no. 7; p. e69240
• Main Authors: Fu, Lingyi, Chen, Wangbing, Guo, Wei, Wang, Jingshu, Tian, Yun, Shi, Dingbo, Zhang, Xiaohong, Qiu, Huijuan, Xiao, Xiangsheng, Kang, Tiebang, Huang, Wenlin, Wang, Shusen, Deng, Wuguo
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.07.2013; Public Library of Science (PLoS)
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Angiogenesis; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; BAX protein; Bcl-2 protein; Berberine; Berberine - pharmacology; Berberine - therapeutic use; Binding; Cancer; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Caspase; Caspases - metabolism; Cell growth; Cell Line, Tumor; Cell migration; Cell morphology; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Colorectal cancer; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Cytochrome; Cytochrome c; Cytochromes c - metabolism; Cytology; Cytosol; Humans; Hydrastis canadensis; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Inhibition; Kinases; Laboratories; Lung cancer; Lung diseases; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lungs; Medical prognosis; Medical treatment; Mitochondria; Molecular modelling; NF-kappa B - metabolism; NF-κB protein; Non-small cell lung carcinoma; Nuclear transport; Oncology; Phosphorylation; Phytochemicals; Poly(ADP-ribose) polymerase; Prostate cancer; Proteins; Raf protein; Rodents; Signal transduction; Signal Transduction - drug effects; Signaling; Stem cells; Telomerase; Telomerase - metabolism; Transcription Factor AP-2 - metabolism; Translocation; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0069240

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.