1. The Antitumor Agent PBT-1 Directly Targets HSP90 and hnRNP A2/B1 and Inhibits Lung Adenocarcinoma Growth and Metastasis
- Author
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Lu-Ping Chow, Tse-Ming Hong, Tzu Chien V. Wang, Crysline Kuan, Kuo Hsiung Lee, Pan-Chyr Yang, Chi-Yuan Chen, Xiaoming Yang, Shuenn Chen Yang, Lin Yi Wei, and Jau Chen Lin
- Subjects
Male ,Lung Neoplasms ,Slug ,Mice, Nude ,Adenocarcinoma of Lung ,Antineoplastic Agents ,Adenocarcinoma ,Article ,Metastasis ,Mice ,8,11,14-Eicosatrienoic Acid ,Cell Movement ,In vivo ,Cell Line, Tumor ,Heat shock protein ,Heterogeneous-Nuclear Ribonucleoprotein Group A-B ,Drug Discovery ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,HSP90 Heat-Shock Proteins ,Pseudopodia ,Neoplasm Metastasis ,Protein kinase B ,biology ,Chemistry ,Cadherins ,medicine.disease ,biology.organism_classification ,Hsp90 ,In vitro ,3. Good health ,Immunology ,Cancer research ,biology.protein ,Molecular Medicine ,Proto-Oncogene Proteins c-akt ,Neoplasm Transplantation - Abstract
Natural products are the major sources of currently available anticancer drugs. We recently reported that phenanthrene-based tylophorine derivative-1 (PBT-1) may be a potential antitumor agent for lung adenocarcinoma. We therefore examined the direct targets of PBT-1 and their effects in inhibiting lung adenocarcinoma. We found that PBT-1 reduced the level of Slug and inhibits the migration, invasion, and filopodia formation of lung adenocarcinoma CL1-5 cells in vitro. In addition, PBT-1 displayed in vivo antitumor and antimetastasis activities against subcutaneous and orthotopic xenografts of CL1-5 cells in nude mice. Chemical proteomics showed that heat shock protein 90 (HSP90) and heterogeneous nuclear ribonucleoproteins A2/B1 (hnRNP A2/B1) bound PBT-1 in CL1-5 cells. Inhibition of HSP90 and hnRNP A2/B1 reduced the activation of AKT and Slug expression. Taken together, these findings suggest that PBT-1 binds to HSP90 and/or hnRNP A2/B1 and initiates antitumor activities by affecting Slug- and AKT-mediated metastasis and tumorigenesis.
- Published
- 2014