Negative regulation of thyroid adenoma-associated protein (THADA) in the cardiac glycoside-induced anti-cancer effect

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Cardiac glycosides inhibit Na+,K+-ATPase and exhibit anti-cancer properties, including suppressing proliferation and inducing cell death.
• The specific signaling pathways targeted by cardiac glycosides in cancer remain under investigation.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying the anti-proliferative effects of cardiac glycosides in human cancer cell lines.
• To investigate the roles of thyroid adenoma-associated protein (THADA) and L-type amino acid transporter 1 (LAT1) in cardiac glycoside-induced cancer cell growth inhibition.

Main Methods:

• Utilized human hepatocellular carcinoma (HepG2) and epidermoid carcinoma (KB) cell lines.
• Administered three cardiac glycosides: ouabain, oleandrin, and digoxin.
• Performed gene knockdown and re-expression experiments for THADA.
• Assessed the expression levels of THADA and LAT1.
• Utilized a LAT1 inhibitor (JPH203) to evaluate its effect on cell proliferation.

Main Results:

• Cardiac glycosides inhibited cancer cell proliferation and decreased THADA expression in HepG2 and KB cells.
• THADA knockdown suppressed cancer cell proliferation, which was rescued by THADA re-expression.
• THADA knockdown led to a significant decrease in LAT1 expression.
• Cardiac glycosides also reduced LAT1 expression, and LAT1 inhibition with JPH203 weakened cancer cell proliferation.

Conclusions:

• Cardiac glycosides binding to Na+,K+-ATPase negatively regulates the THADA-LAT1 signaling pathway.
• This negative regulation of the THADA-LAT1 pathway contributes to the anti-proliferative effects of cardiac glycosides in cancer cells.
• The findings suggest THADA and LAT1 as potential therapeutic targets in cardiac glycoside-based cancer treatments.