title: The antitumor agent PBT-1 directly targets HSP90 and hnRNP A2/B1 and inhibits lung adenocarcinoma growth and metastasis.
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.
authors.affiliation: Research Center for Industry of Human Ecology, ‡Graduate Institute of Health Industry Technology, and §Department of Nutrition and Health Sciences, Chang Gung University of Science and Technology , Kwei-San, Tao-Yuan, Taiwan.
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Chen
authors.forename: Shuenn-Chen
authors.initials: SC
authors.lastname: Yang
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Yang
authors.forename: Lin-Yi
authors.initials: LY
authors.lastname: Wei
authors.forename: Lu-Ping
authors.initials: LP
authors.lastname: Chow
authors.forename: Tzu-Chien V
authors.initials: TC
authors.lastname: Wang
authors.forename: Tse-Ming
authors.initials: TM
authors.lastname: Hong
authors.forename: Jau-Chen
authors.initials: JC
authors.lastname: Lin
authors.forename: Crysline
authors.initials: C
authors.lastname: Kuan
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011554:Pseudopodia / Q000187:drug effects / Q000473:pathology
chemical_list: C454099:8-hydroxy-11,12-cyclopropyleicosa-5,9,14-trienoic acid methyl ester; D000970:Antineoplastic Agents; D015820:Cadherins; D018841:HSP90 Heat-Shock Proteins; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D051057:Proto-Oncogene Proteins c-akt; D015126:8,11,14-Eicosatrienoic Acid