Peroxisome proliferator-activated receptorδ (PPARδ) belongs to the PPARs receptor family including PPARα, PPARδ, and PPARγ. PPARδ is a ligand-activated transcription factor that plays a critical role in regulating cancer progression. PPARδ-linked tumorigenesis was first identified in colorectal cancer, which is demonstrated by the following evidences, so PPARε is a potential drug target for colorectal cancer. In contrast, some observations show that PPARδ negatively regulates colorectal cancer event. In the present review, the recent progress of PPARδ signaling-mediated colorectal cancer is covered.

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.

The nuclear factor kB (NFkB) transcription factor plays critical roles in inflammation and immunity. The dysregulation of NFkB is associated with inflammatory and autoimmune diseases and cancer. NFkB activation is negatively regulated by the ubiquitin-dependent proteasomal degradation pathway. In the present review, we discuss recent advances in our understanding of how ubiquitin ligases regulate the NFkB degradation pathway. Keywords: NFkB; ubiquitination; degradation; pathway Nuclear factor kB (NFkB) was identified approximately 20 years ago by Dr David Baltimore as a transcription factor that binds to the intronic enhancer of the kappa light chain gene (the kB site) in B cells. 1 The NFkB family is composed of several members including p50, p52, p65/RelA, c-Rel and RelB and plays a central role in cell growth, inflammation, immunity and apoptosis. NFkB activation is dependent on the stability of the inhibitor IkBa. IkBa stabilizes the NFkB complex so that after its degradation the remaining subunits translocate from the cytoplasm to the nucleus. 2 The phosphorylation of IkBa is catalyzed by IkB kinase (IKK), a complex composed of three subunits: IKKa/IKK1, IKKb/IKK2, and IKKc/NEMO. IKK1 and IKK2 are the catalytic subunits, whereas IKKc serves as a non-enzymatic regulator. [3][4][5] The IKKs/NFkB pathway is activated by extracellular stimuli such as cytokines, ultraviolet irradiation, free radicals, bacterial or viral antigens and oxidized low density lipoprotein. 3,4 In the absence of persistent upstream stimuli, NFkB transcriptional activity is terminated by the NFkB/IkBa negative feedback loop. 4 The activation of NFkB in immune or stromal cells causes a pro-inflammatory response, and persistent tissue inflammation has been linked to inflammation-associated cancer. 6 NFkB activation is negatively regulated by ubiquitin-dependent proteasomal degradation. 7-9 The ubiquitin-proteasome system comprises a ubiquitin-activating enzyme (E1), a ubiquitinconjugating enzyme (E2) and a ubiquitin ligase (E3). Ubiquitin E3 ligases play a critical role in substrate recognition and polyubiquitination by recruiting E2 ubiquitin-conjugating enzymes to specific substrates. 10 SOCS-1 (suppressor of cytokine signaling) is one of the components of the EC 2 S (Elongin BC-CUL2-SOCS-box protein) ubiquitin ligase complex that mediates JAK2 (Janus kinase 2) ubiquitination and degradation. 11,12 Similar to JAK2, NFkB/p65 is also a substrate of the EC 2 S ubiquitin ligase complex in both mice and cancer cells. 13 Pin1 increases NFkB/p65 stability and transactivation, while the loss of Pin1 leads to SOCS-1-mediated p65 ubiquitination and degradation. 13 This offers a new mechanism for NFkBmediated pathogenesis.NFkB is also activated by viral infections. In immunodeficiency virus-1-infected CD4 1 lymphocytes, NFkB activation is terminated by COMMD1 (MURR1), resulting in the inhibition of immunodeficiency virus-1 growth in unstimulated or cytokine-stimulated CD4 1 T cells. 14 This study demonstrated that COMMD1 decreases NFkB transcriptio...

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PPARα (peroxisome-proliferator-activated receptor α) plays a critical role in regulation of inflammation and cancer, while the regulatory mechanism of PPARα on cancer cell autophagy is still unclear. Here we found that PPARα enhanced autophagy in HEK293T, SW480, and Hela cell lines, which was independent of PPARα transcription activity. PPARα induced antiapoptotic Bcl2 protein degradation resulting in release of the Beclin-1/VPS34 complex. Consistently, silenced PPARα reversed this event. PPARα-induced autophagy significantly inhibited tumor growth and enhanced SW480 cancer cell sensitivity to chemotherapy drugs. Moreover, PPARα agonist increased SW480 cancer cell chemotherapy sensitivity. These findings revealed a novel mechanism of PPARα/Bcl2/autophagy pathway suppressed tumor progression and enhanced chemotherapy sensitivity, which is a potential drug target for cancer treatment.