ACE Loss Drives Renal Cell Carcinoma Growth and Invasion by Modulating AKT-FOXO1

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• The renin-angiotensin-aldosterone system (RAAS) is implicated in cancer progression.
• The specific role of RAAS in clear-cell renal cell carcinoma (ccRCC) remains unverified.

Purpose of the Study:

• To investigate the expression and function of Angiotensin-Converting Enzyme (ACE), a key RAAS component, in ccRCC.
• To elucidate the underlying mechanisms of ACE in ccRCC progression and its potential as a therapeutic target.

Main Methods:

• Quantitative RT-PCR, Western blot, and immunohistochemistry for ACE expression analysis.
• Cell proliferation, migration, invasion, and glycolysis assays (CCK-8, Transwell, Seahorse).
• Xenograft models, RNA-seq, ChIP, and luciferase reporter assays to explore molecular mechanisms.

Main Results:

• ACE was significantly underexpressed in ccRCC tissues and cell lines.
• High ACE expression was associated with favorable patient prognosis.
• ACE overexpression suppressed ccRCC cell growth, metastasis, and glycolysis, while knockdown enhanced these processes.
• ACE inhibited ccRCC progression and epithelial-mesenchymal transition (EMT) via the AKT-FOXO1 signaling pathway.
• ACE enhanced the antitumor effect of everolimus and its expression is regulated by ZBTB26.

Conclusions:

• ACE plays an inhibitory role in ccRCC progression, growth, and metastasis.
• ACE exerts its effects by promoting FOXO1 expression, a downstream target of the PI3K-AKT pathway.
• ACE represents a potential therapeutic target for ccRCC treatment.