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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
8,11,14-Eicosatrienoic Acid / analogs & derivatives*
-
8,11,14-Eicosatrienoic Acid / pharmacology
-
8,11,14-Eicosatrienoic Acid / therapeutic use
-
Adenocarcinoma / drug therapy
-
Adenocarcinoma / metabolism
-
Adenocarcinoma / pathology*
-
Adenocarcinoma of Lung
-
Animals
-
Antineoplastic Agents / pharmacology*
-
Antineoplastic Agents / therapeutic use
-
Cadherins / metabolism
-
Cell Line, Tumor
-
Cell Movement / drug effects
-
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
-
HSP90 Heat-Shock Proteins / metabolism
-
Heterogeneous-Nuclear Ribonucleoprotein Group A-B / antagonists & inhibitors*
-
Heterogeneous-Nuclear Ribonucleoprotein Group A-B / metabolism
-
Humans
-
Lung Neoplasms / drug therapy
-
Lung Neoplasms / metabolism
-
Lung Neoplasms / pathology*
-
Male
-
Mice
-
Mice, Nude
-
Neoplasm Invasiveness / prevention & control
-
Neoplasm Metastasis
-
Neoplasm Transplantation
-
Proto-Oncogene Proteins c-akt / metabolism
-
Pseudopodia / drug effects
-
Pseudopodia / pathology
Substances
-
8-hydroxy-11,12-cyclopropyleicosa-5,9,14-trienoic acid methyl ester
-
Antineoplastic Agents
-
Cadherins
-
HSP90 Heat-Shock Proteins
-
Heterogeneous-Nuclear Ribonucleoprotein Group A-B
-
Proto-Oncogene Proteins c-akt
-
8,11,14-Eicosatrienoic Acid