D-ribose-5-phosphate inactivates YAP and functions as a metabolic checkpoint

Area of Science:

• Cancer Metabolism
• Molecular Oncology
• Metabolic Checkpoints

Background:

• Targeting glucose transporter (GLUT) inhibitors is a potential cancer therapy, but clinical success is limited.
• The mechanisms underlying cancer cell survival under glucose limitation are not fully understood.

Purpose of the Study:

• To identify key metabolic changes enabling cancer cell survival during glucose limitation.
• To elucidate the mechanism of metabolic adaptation to glucose deprivation in cancer.

Main Methods:

• Western blotting and Phos-tag immunoblotting for YAP phosphorylation analysis.
• Targeted metabolomics (600MRM) to analyze metabolic changes.
• In vivo studies using APC^min/+ mice and in vitro assays to examine anti-cancer roles.

Main Results:

• D-Ribose-5-phosphate (D5P), a pentose phosphate pathway product, acts as a metabolic checkpoint activating YAP under glucose limitation.
• Decreased D5P facilitates MYH9-mediated LATS1 degradation, leading to YAP activation.
• Activated YAP promotes purine nucleoside phosphorylase (PNP)-mediated D5P restoration, creating a feedback loop.

Conclusions:

• D5P links glucose limitation stress to YAP activation, serving as a critical metabolic checkpoint.
• D5P enhances sensitivity to GLUT inhibitors and shows potential as an anti-cancer metabolite.