Direct targeting of HSP90 with daurisoline destabilizes β-catenin to suppress lung cancer tumorigenesis

Area of Science:

• Natural Product Chemistry
• Oncology
• Molecular Biology

Background:

• Lung cancer is a leading cause of cancer mortality worldwide, necessitating the discovery of novel therapeutic agents.
• Current treatments for lung cancer often have significant toxicities, highlighting the urgent need for safer and more effective strategies.
• Natural products represent a rich source of potential anticancer compounds.

Purpose of the Study:

• To screen a library of natural products for anticancer activity against lung cancer.
• To investigate the mechanism of action of a promising compound, daurisoline, in lung cancer.
• To evaluate the therapeutic potential of daurisoline as a novel lung cancer treatment.

Main Methods:

• Screening of 429 natural products for antiproliferative activity.
• Cell cycle analysis, migration, and invasion assays in lung cancer cell lines.
• Quantitative proteomics, Western blotting, qRT-PCR, DARTS, and ITC to elucidate the molecular mechanism.
• In vivo studies using lung tumor xenografts in animal models.

Main Results:

• Daurisolne significantly repressed lung cancer cell proliferation by inducing G1 phase cell cycle arrest.
• Daurisolne suppressed tumor growth in vivo without observable side effects and inhibited cell migration and invasion.
• Daurisolne was found to directly target Heat Shock Protein 90 (HSP90), disrupting its interaction with β-catenin.
• This interaction disruption led to increased ubiquitin-mediated proteasomal degradation of β-catenin, downregulating c-myc and cyclin D1 expression.

Conclusions:

• Daurisolne exhibits significant anticancer properties against lung cancer through the inhibition of the HSP90/β-catenin pathway.
• Daurisolne demonstrates potential as a novel, low-toxicity therapeutic strategy for lung cancer treatment.
• Targeting the HSP90-β-catenin interaction represents a promising avenue for developing new lung cancer therapies.