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

Peroxisome proliferator-activated receptor delta (PPAR delta) is a nuclear receptor transcription factor that plays an important role in the regulation of metabolism, inflammation, and cancer. In addition, the nutrient-sensing kinase 5'AMP-activated protein kinase (AMPK) is a critical regulator of cellular energy in coordination with PPAR delta. However, the molecular mechanism of the AMPK/PPAR delta pathway on cancer progression is still unclear. Here, we found that activated AMPK induced PPAR delta-S50 phosphorylation in cancer cells, whereas the PPAR delta/S50A (nonphosphorylation mimic) mutant reversed this event. Further analysis showed that the PPAR delta/S50E (phosphorylation mimic) but not the PPAR delta/S50A mutant increased PPAR delta protein stability, which led to reduced p62/SQSTM1-mediated degradation of misfolded PPAR delta. Furthermore, PPAR delta-S50 phosphorylation decreased PPAR delta transcription activity and alleviated PPAR delta-mediated uptake of glucose and glutamine in cancer cells. Soft agar and xenograft tumor model analysis showed that the PPAR delta/S50E mutant but not the PPAR delta/S50A mutant inhibited colon cancer cell proliferation and tumor growth, which was associated with inhibition of Glut1 and SLC1A5 transporter protein expression. These findings reveal a new mechanism of AMPK-induced PPAR delta-S50 phosphorylation, accumulation of misfolded PPAR delta protein, and inhibition of PPAR delta transcription activity contributing to the suppression of colon tumor formation.

Automated summary

The study found that AMPK-induced PPARδ-S50 phosphorylation, accumulation of misfolded PPARδ protein, and inhibition of PPARδ transcription activity can suppress colon tumor formation.