Establishing the Role of PPARβ/δ in Carcinogenesis

Abstract

The role of the nuclear hormone receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in carcinogenesis is controversial because conflicting studies indicate that PPARβ/δ inhibits and promotes tumorigenesis. This review focuses on recent studies on PPARβ/δ including: 1) the significance of increased or decreased PPARβ/δ expression in cancers, 2) a range of opposing mechanisms describing how PPARβ/δ agonists, antagonists and inverse agonists regulate tumorigenesis and/or whether there may be cell context-specific mechanisms, and 3) whether activating or inhibiting PPARβ/δ is feasible for cancer chemoprevention and/or therapy. Research questions that need to be addressed will be highlighted in order to establish whether PPARβ/δ can be effectively targeted for cancer chemoprevention.

Ligand activation of peroxisome proliferator-activated receptor-β/δ suppresses liver tumorigenesis in hepatitis B transgenic mice

“…Results from published studies examining other cancer models also show that ligand activation of PPARβ/δ inhibits pre-neoplastic stages including steatosis, cell proliferation and inflammation, which contribute to the progression of hepatocellular carcinoma (reviewed in (Peters et al 2015; Peters et al 2011; Peters et al 2012)). This is consistent with results from the present study that also demonstrate that ligand activation of PPARβ/δ inhibits steatosis, together with gene expression linked with cell proliferation, inflammation and promotion of apoptosis in the liver of HBV mice.…”

“…Previous work has shown that ligand activation of PPARβ/δ can promote terminal differentiation, which is known to be associated with a concomitant withdrawal from the cell cycle (reviewed in (Peters et al 2015; Peters et al 2011; Peters et al 2012)). Other studies have demonstrated that ligand activation of PPARβ/δ can inhibit cell proliferation by causing a block in mitosis (Zhu et al 2012).…”

PPARs and nonalcoholic fatty liver disease

“…This study was limited by the small number of patients, short duration, and extensive exclusion criteria, reducing generalizability of the results. Of note, in 2007, further clinical development of GW501516 for all uses was abandoned due to development of cancer in preclinical models [59,64,65]. …”

“…Overall, at this time, data regarding the effectiveness of any PPARδ agonist for the treatment of NAFLD remains too limited to formulate conclusions. With regards to safety concerns, the role of PPARδ in carcinogenesis remains controversial as there are conflicting studies in in vitro studies as well as preclinical and clinical studies [59,64]. …”

Peroxisome Proliferator-Activated Receptor Modulation during Metabolic Diseases and Cancers: Master and Minions

“…In particular, PPAR δ , through its anti-inflammatory effects, seems to prevent cancer before its development; conversely, after the development of cancer, the activation of PPAR δ promotes angiogenesis and cancer growth [76]. Clinical data suggest a strong association between PPAR δ and aggressive cancer; in particular, inverse correlation of PPAR δ expression with survival in gastrointestinal cancer has been noted [77].…”