PPARα Promotes Cancer Cell Glut1 Transcription Repression

Abstract

Abundant nutrient availability including glucose and amino acids plays an important role in maintaining cancer cell energetic and biosynthetic pathways. As a nuclear receptor, peroxisome-proliferator-activated receptor α (PPARα) regulates inflammation and cancer progression, however, it is still unclear the interaction of PPARα with the cancer cell glucose metabolism. Here we found that PPARα reduced Glut1 (Glucose transporter 1) protein and gene levels in HCT-116, SW480, HeLa, and MCF-7 cancer cell lines. In contrast, silenced PPARα reversed this event. Further analysis shows that PPARα directly targeted the consensus PPRE motif of Glut1 promoter region resulting in Glut1 transcription repression. PPARα-mediated Glut1 transcription repression led to decreased influx of glucose in cancer cells. These findings revealed a novel mechanism of PPARα-mediated cancer cell Glut1 transcription repression. J. Cell. Biochem. 118: 1556-1562, 2017. © 2016 Wiley Periodicals, Inc.

Hippocampal PPARα is a novel therapeutic target for depression and mediates the antidepressant actions of fluoxetine in mice

“…The immunofluorescence results indicated that chronic stress induced global changes of hippocampal PPARα distribution. As a nuclear receptor, PPARα has the main physiological function of modulating the transcriptional activities of some genes, including those for Glut1, CREB, Mogat1 and HO‐1, by binding PPREs (Roy et al ., ; Sankella et al ., ; Wu et al ., ; You et al ., ). Among these genes, CREB is well known to participate in depression (Blendy, ; Gass and Riva, ; Krishnan and Nestler, ).…”

Peroxisome proliferator-activated receptors (PPARs) are potential drug targets for cancer therapy

“…Even though the PPARs family contains PPARα, PPARγ and PPARδ, they serve as different functions in tumor development. Increasing evidences show that PPARα [ 2 , 10 – 12 ] or PPARγ [ 7 , 8 , 13 ] inhibits tumor progression, which acts as tumor suppressors, while some reports show that PPARα is associated with tumor progression [ 14 – 16 ]. In contrast, PPARδ promotes tumor development [ 3 , 6 , 17 ].…”

“…Glut1 plays a critical role in glucose uptake to regulate cancer cell metabolism, which is widely expressed in most types of cancer cells [ 24 , 25 ]. PPARα can directly inhibit Glut1 transcription by binding Glut1 potential PPRE motif [ 2 ]. The synthetic ligands of PPARα including fenofibrate, clofibrate and wyeth14,643 suppress cell proliferation by inducing apoptosis and cell cycle arrest involved in inhibition of NFκB [ 26 ] and activation of caspase-3 [ 26 , 27 ].…”

The Involvement of PPARs in the Peculiar Energetic Metabolism of Tumor Cells

“…Otherwise, fenofibrate could increased FAO resulting in high acyl group levels useful for TCA reaction [126,129]. Regarding to Warburg effect and related glycolysis, it was reported the repression activity of PPARα on GLUT1 gene with reduced glucose uptake, these evidences were obtained in different cancer cell line (HCT-116, SW480, MCF-7 and HeLa) [70].…”

“…To date research activity has yielded conflicting evidence in this regard. There are different results about the tumour suppression related to PPARα and PPARγ transcriptional activation [64][65][66][67][68][69][70], but likewise proofs of their cancer promotion activity [71][72][73]; instead regarding PPARβ/δ activity the majority of study conducted shows its oncogenic role [74][75][76]. Although it must be emphasized that PPARs behaviour, both as pro-or anti-tumour, is strictly dependent on the tissue type and tumour microenvironment.…”