Suppression of p16 Induces mTORC1-Mediated Nucleotide Metabolic Reprogramming

Area of Science:

• Oncology
• Cell Biology
• Metabolic Pathways

Background:

• Cell cycle dysregulation and metabolic reprogramming are key cancer hallmarks.
• p16, a cell cycle inhibitor and tumor suppressor, is upregulated during oncogene-induced senescence (OIS).
• Loss of p16 function enables cell cycle progression, OIS bypass, and tumorigenesis, but its metabolic impact is unclear.

Purpose of the Study:

• To investigate the role of p16 suppression in metabolic reprogramming in cancer.
• To elucidate the molecular mechanisms linking p16 loss to altered cellular metabolism.
• To identify potential metabolic vulnerabilities in p16-deficient cancers.

Main Methods:

• Analysis of p16 expression and its correlation with metabolic markers.
• Investigating the activation of mTORC1 signaling and its downstream targets.
• Assessing the impact of RPIA suppression on cell proliferation and senescence.
• In vitro and in vivo studies in cancer models.

Main Results:

• p16 suppression is a key driver of metabolic reprogramming, specifically increasing nucleotide synthesis.
• Activation of the mTORC1 signaling pathway directly upregulates the translation of ribose-5-phosphate isomerase A (RPIA).
• The mTORC1-RPIA axis is activated in p16-low cancers across multiple types.
• Suppression of RPIA inhibits proliferation in p16-low cells by inducing senescence.

Conclusions:

• p16 loss modulates pro-tumorigenic metabolism through mTORC1-mediated upregulation of nucleotide synthesis.
• This study reveals a molecular link between cell cycle control and metabolic adaptation in cancer.
• Targeting RPIA represents a potential therapeutic strategy for p16-null cancers, exploiting their metabolic vulnerability.