Peroxisome proliferator-activated receptors as therapeutic target for cancer

Abstract

Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor family. There are three subtypes of PPARs, including PPAR-α, PPAR-β/δ and PPAR-γ. They are expressed in different tissues and act by regulating the expression of target genes in the form of binding to ligands. Various subtypes of PPAR have been shown to have significant roles in a wide range of biological processes including lipid metabolism, body energy homeostasis, cell proliferation and differentiation, bone formation, tissue repair and remodelling. Recent studies have found that PPARs are closely related to tumours. They are involved in cancer cell growth, angiogenesis and tumour immune response, and are essential components in tumour progression and metastasis. As such, they have become a target for cancer therapy research. In this review, we discussed the current state of knowledge on the involvement of PPARs in cancer, including their role in tumourigenesis, the impact of PPARs in tumour microenvironment and the potential of using PPARs combinational therapy to treat cancer by targeting essential signal pathways, or as adjuvants to boost the effects of current chemo and immunotherapies. Our review highlights the complexity of PPARs in cancer and the need for a better understanding of the mechanism in order to design effective cancer therapies.

Keywords: PPARs; cancer; combinational therapy; therapeutic targets; tumor microenvironment.

FIGURE 1

Activation of peroxisome proliferator‐activated receptors (PPARs). Upon activation, PPARs form heterodimers with nuclear receptors by binding to their ligands. The heterodimers then bind to peroxisome proliferator response elements (PPREs) in the promoter region, which regulates the expression of downstream target genes. These genes play crucial roles in various biological processes, such as lipid metabolism, body energy homeostasis and tumourigenesis. Figure was generated with BioRender.

FIGURE 2

Roles of peroxisome proliferator‐activated receptors (PPARs) in tumourigenesis. Act as nuclear receptor, PPARs regulate lipid metabolism and are involved in tumour progression. (A) The isoform PPAR‐α regulates nuclear receptor NF‐κB and COX‐2‐related metabolism progression. PPAR‐α mainly plays an antitumour role during tumour progression. (B) The isoform PPAR‐γ increases ATP level through AKT involved signalling and reduces the expression of COX‐2/vascular endothelial growth factor (VEGF) by inhibiting AP‐1. PPAR‐γ mainly acts as a tumour promoter during tumour progression. (C) The isoform PPAR‐β/δ affects AKT mediated signalling and plays controversial roles in tumourigenesis. Figure was generated with BioRender.

FIGURE 3

Role of peroxisome proliferator‐activated receptors (PPARs) in tumour inflammation. (A) PPARs serve as transcriptional regulators directly or indirectly repressing the expression of proinflammatory genes. Top, PPAR‐γ binds NF‐κB thus affect the transcription of the genes regulated by NF‐κB; middle, PPAR‐α binds transcription factors thus interfere the expression of IL‐6, the NF‐κB subunit p65, c‐Jun and c‐AMP response element‐binding protein‐binding protein (CBP); bottom, ligands activated PPAR‐β/δ releases BCL‐6 thus transrepress the expression of inflammatory genes. (B) PPARs are activated by lipid ligands further regulating the production of inflammatory factors. PPAR‐α is activated by FAs then translocate to nuclear repress the transcription of proinflammatory genes. In contrast, FAs activated PPAR‐δ induced the production of COX2 and PEG₂ thus promoted the inflammation. Figure was generated with BioRender.

FIGURE 4

Role of peroxisome proliferator‐activated receptors (PPARs) in tumour microenvironment. (A) PPARs reprogram the metabolism of fibroblasts. overexpression of PPAR‐γ reprogrammed cancer‐associated fibroblasts to the autophagic and glycolytic metabolism, which accelerates tumour growth. PPAR‐β/δ activate LRG1 which interferes with TGF‐β1‐dependent redox homeostasis, resulting in oncogenic transformation in the surrounding epithelium. (B) In the endothelial cells, PPAR‐α exhibits an anti‐angiogenic effect by promoting anti‐angiogensis genes and inhibiting pro‐angiogenesis factors, while PPAR‐β/δ is more pro‐angiogenic, promoting endothelial proliferation and vascular maturation. (C) PPARs prime anti‐inflammatory M2‐like macrophage polarisation which causes anti‐inflammatory response; PPARs regulate DCs lipid metabolism, resulting in immune dysfunction. (D) PPARs involve in activation, differentiation, metabolic reprogramming of T cell and B cell. Figure was generated with BioRender.

FIGURE 5

Schematic overview of the interaction of peroxisome proliferator‐activated receptor (PPAR) agonists with key signalling pathways. PPAR‐γ agonist enhance the expression of PTEN, which subsequently inhibits PI3K/AKT/mTORC1 pathway, resulting reduced tumour expansion and progression. Additionally, PPAR‐γ agonist can also downregulate the expression of STAT5 expression and its downstream targets, HIF2a and CITED2, promoting tumour quiescence. When combined with RXR agonist, PPAR‐γ agonist can potentiate their effects, leading to decreased cell proliferation and increased apoptosis by regulating the transcriptional activity of genes controlling these processes. On the other hand, PPAR‐α agonist, contribute to anticancer activity by elevating reactive oxygen species levels and inhibiting IGF‐I receptor signalling, thereby hindering tumour growth. Figure was generated with BioRender.