PPARδ rewires cellular metabolism regulating MYC/PGC1A balance. A, Expression of MYC, PGC1A, and MYC/PGC1A ratio in PDX-354 after mitochondrial energy deprivation during 48 to 72 hours (n = 4–7). B,MYC and PGC1A reporter assay. Promoter activity was estimated as luciferase bioluminescence at the indicated times following treatment with PPARδ agonist GW0742 or PPARD overexpression (PPARD OE; n = 3–5). C, PDAC-354 cells were transduced with inducible lentiviral vectors expressing either a nontargeting short hairpin RNA (NT shRNA) or two different shRNAs against MYC (sh#1 and sh#2) or the complete cDNA of PGC1A. Effect of MYC knockdown (shMYC, pooled data for sh#1 and sh#2) or PGC1A overexpression (PGC1A OE) on invasiveness in response to treatment with 5 μmol/L PPARδ agonist L-165 for 48 hours (n = 6–8). D, CUT left) and ATP-linked respiration (n = 4; right). F, Glycolytic (Glyco) capacity (left) and reserve (n = 4; right). G,ZEB1 gene expression. H, Invasive capacity (n = 10). I, PDAC-354 cells were treated with MCM or 20 μmol/L etomoxir for 48 hours in the presence or absence of the MYC/Max interaction inhibitor Mycro3 (25 μmol/L). Cells were then seeded in modified Boyden invasion chambers containing 20% FBS in the lower compartment. The number of invasive cells was assessed after 16 hours (n = 5). In E, F, and H, the bars represent pooled data from PDAC-215 and 354, showing individual data points corresponding to each PDX. All data are represented as the mean ± SEM. #, P P P P P P
Parejo-Alonso et al. (Tue,) studied this question.