Anti-oral Squamous Cell Carcinoma Effects of a Potent TAZ Inhibitor AR-42

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Oral squamous cell carcinoma (OSCC) remains a significant global health challenge with low survival rates.
• The TAZ protein, a Hippo pathway effector, is upregulated in OSCC and represents a potential therapeutic target.
• Existing treatments for OSCC have limitations, highlighting the need for novel therapeutic strategies.

Purpose of the Study:

• To identify and evaluate a potential therapeutic agent for oral squamous cell carcinoma (OSCC).
• To investigate the efficacy of a novel TAZ inhibitor, AR-42, in preclinical models of OSCC.
• To elucidate the mechanisms by which AR-42 exerts its anti-cancer effects in OSCC.

Main Methods:

• Development of a stable transfected cell line (HEK293-TAZ) for high-throughput screening.
• Utilized dual-luciferase reporter assays to identify TAZ inhibitors.
• Assessed AR-42's effects on OSCC cell viability, proliferation, apoptosis, cell cycle, invasion, and sphere-forming capacity.
• Investigated AR-42's impact on TAZ/YAP protein levels and transcriptional activity.
• Evaluated AR-42 efficacy in an OSCC xenograft mouse model.

Main Results:

• AR-42 was identified as a potent TAZ inhibitor.
• AR-42 significantly suppressed OSCC cell viability, proliferation, invasion, and sphere formation.
• AR-42 induced apoptosis and G2/M cell cycle arrest in OSCC cells.
• AR-42 reduced TAZ and YAP protein levels by inhibiting transcription and promoting degradation.
• AR-42 demonstrated anti-tumor activity in vivo in an OSCC xenograft model.

Conclusions:

• AR-42 exhibits significant anti-cancer properties against oral squamous cell carcinoma (OSCC) by targeting TAZ.
• AR-42 effectively inhibits OSCC cell proliferation, invasion, metastasis, and cancer stem cell properties.
• AR-42 warrants further investigation as a potential therapeutic drug candidate for OSCC treatment.