pNaktide reverses metabolic reprogramming and disease progression of ATP1A1-deficiency clear cell renal cell...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• ATP1A1 (Na+/K+-transporting ATPase alpha 1 subunit) expression varies in tumors, but its role in clear cell renal cell carcinoma (ccRCC) is unknown.
• Investigating ATP1A1 in ccRCC is crucial for identifying prognostic markers and therapeutic targets.

Purpose of the Study:

• To elucidate the role of ATP1A1 in ccRCC pathogenesis.
• To assess ATP1A1 as a prognostic indicator and therapeutic target in ccRCC.
• To evaluate the therapeutic potential of pNaktide, an ATP1A1-mimicking peptide.

Main Methods:

• Database analysis and clinical sample evaluation to assess ATP1A1 expression in ccRCC.
• In vitro and in vivo experiments to determine ATP1A1's functional role and the effects of pNaktide.
• Co-expression gene analysis to identify pathways regulated by ATP1A1.
• Nude mouse models to evaluate pNaktide's efficacy in reducing tumor growth.

Main Results:

• ATP1A1 expression is significantly downregulated in ccRCC, correlating with poor prognosis.
• ATP1A1 exhibits tumor-suppressive effects by inhibiting SRC kinase activity and promoting metabolic reprogramming from glycolysis to oxidative phosphorylation (OXPHOS).
• Overexpression of ATP1A1 increases reactive oxygen species (ROS), inducing apoptosis.
• pNaktide effectively inhibits ccRCC proliferation in vitro and in vivo by suppressing SRC signaling and altering metabolism, significantly reducing tumor volume and weight in mouse models.

Conclusions:

• Reduced ATP1A1 expression is a key driver of ccRCC progression.
• pNaktide demonstrates significant therapeutic potential for ccRCC by restoring ATP1A1-like functions.
• Targeting ATP1A1 or its functional mimics represents a promising therapeutic strategy for ccRCC.