The antitumor agent PBT-1 directly targets HSP90 and hnRNP A2/B1 and inhibits lung adenocarcinoma growth and metastasis

Chi Yuan Chen, Shuenn Chen Yang, Kuo Hsiung Lee, Xiaoming Yang, Lin Yi Wei, Lu Ping Chow, Tzu Chien V Wang, Tse-Ming Hong, Jau Chen Lin, Crysline Kuan, Pan Chyr Yang

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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.

Original languageEnglish
Pages (from-to)677-685
Number of pages9
JournalJournal of Medicinal Chemistry
Volume57
Issue number3
DOIs
Publication statusPublished - 2014 Feb 13

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Heterogeneous-Nuclear Ribonucleoprotein Group A-B
HSP90 Heat-Shock Proteins
Antineoplastic Agents
Neoplasm Metastasis
Gastropoda
Growth
Pseudopodia
Biological Products
Heterografts
Nude Mice
Proteomics
phenanthrene
tylophorine
Adenocarcinoma of lung
Carcinogenesis

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Chen, Chi Yuan ; Yang, Shuenn Chen ; Lee, Kuo Hsiung ; Yang, Xiaoming ; Wei, Lin Yi ; Chow, Lu Ping ; Wang, Tzu Chien V ; Hong, Tse-Ming ; Lin, Jau Chen ; Kuan, Crysline ; Yang, Pan Chyr. / The antitumor agent PBT-1 directly targets HSP90 and hnRNP A2/B1 and inhibits lung adenocarcinoma growth and metastasis. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 3. pp. 677-685.
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Chen, CY, Yang, SC, Lee, KH, Yang, X, Wei, LY, Chow, LP, Wang, TCV, Hong, T-M, Lin, JC, Kuan, C & Yang, PC 2014, 'The antitumor agent PBT-1 directly targets HSP90 and hnRNP A2/B1 and inhibits lung adenocarcinoma growth and metastasis', Journal of Medicinal Chemistry, vol. 57, no. 3, pp. 677-685. https://doi.org/10.1021/jm401686b

The antitumor agent PBT-1 directly targets HSP90 and hnRNP A2/B1 and inhibits lung adenocarcinoma growth and metastasis. / Chen, Chi Yuan; Yang, Shuenn Chen; Lee, Kuo Hsiung; Yang, Xiaoming; Wei, Lin Yi; Chow, Lu Ping; Wang, Tzu Chien V; Hong, Tse-Ming; Lin, Jau Chen; Kuan, Crysline; Yang, Pan Chyr.

In: Journal of Medicinal Chemistry, Vol. 57, No. 3, 13.02.2014, p. 677-685.

Research output: Contribution to journalArticle

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T1 - The antitumor agent PBT-1 directly targets HSP90 and hnRNP A2/B1 and inhibits lung adenocarcinoma growth and metastasis

AU - Chen, Chi Yuan

AU - Yang, Shuenn Chen

AU - Lee, Kuo Hsiung

AU - Yang, Xiaoming

AU - Wei, Lin Yi

AU - Chow, Lu Ping

AU - Wang, Tzu Chien V

AU - Hong, Tse-Ming

AU - Lin, Jau Chen

AU - Kuan, Crysline

AU - Yang, Pan Chyr

PY - 2014/2/13

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N2 - 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.

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