AMPK phosphorylates PPARδ to mediate its stabilization, inhibit glucose and glutamine uptake and colon tumor growth

Area of Science:

• Cellular Biology
• Molecular Oncology
• Metabolic Regulation

Background:

• Peroxisome proliferator-activated receptor delta (PPARδ) is a nuclear receptor involved in metabolism, inflammation, and cancer.
• 5'AMP-activated protein kinase (AMPK) is a key regulator of cellular energy, coordinating with PPARδ.
• The precise molecular mechanism linking AMPK and PPARδ in cancer progression remains elusive.

Purpose of the Study:

• To elucidate the molecular mechanism of the AMPK/PPARδ pathway in colon cancer progression.
• To investigate the role of PPARδ phosphorylation at serine 50 (S50) in cancer cell metabolism and tumor growth.

Main Methods:

• Utilized cancer cell lines and phosphorylation mimic/non-mimic mutants (PPARδ-S50E and PPARδ-S50A).
• Assessed protein stability, degradation pathways (p62/SQSTM1), and transcriptional activity.
• Evaluated glucose and glutamine uptake, soft agar assays, and xenograft tumor models in mice.

Main Results:

• Activated AMPK induced PPARδ-S50 phosphorylation, increasing PPARδ protein stability by inhibiting its degradation.
• PPARδ-S50 phosphorylation reduced PPARδ transcriptional activity and suppressed glucose and glutamine uptake in cancer cells.
• The PPARδ-S50E mutant inhibited colon cancer cell proliferation and tumor growth, correlating with reduced Glut1 and SLC1A5 expression.

Conclusions:

• AMPK-induced PPARδ-S50 phosphorylation represents a novel mechanism for suppressing colon tumor formation.
• This pathway involves increased PPARδ protein stability, reduced transcriptional activity, and inhibited nutrient transporter expression.
• Targeting the AMPK/PPARδ pathway offers a potential strategy for colon cancer therapy.