The Antitumor Agent PBT‑1 Directly Targets HSP90 and hnRNP A2/B1 and Inhibits Lung Adenocarcinoma Growth and Metastasis

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.