Anti- and Protumorigenic Effects of PPARγ in Lung Cancer Progression: A Double-Edged Sword

Abstract

Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear receptor superfamily of ligand-activated transcription factors that plays an important role in the control of gene expression linked to a variety of physiological processes, including cancer. Ligands for PPARγ include naturally occurring fatty acids and the thiazolidinedione class of antidiabetic drugs. Activation of PPARγ in a variety of cancer cells leads to inhibition of growth, decreased invasiveness, reduced production of proinflammatory cytokines, and promotion of a more differentiated phenotype. However, systemic activation of PPARγ has been reported to be protumorigenic in some in vitro systems and in vivo models. Here, we review the available data that implicate PPARγ in lung carcinogenesis and highlight the challenges of targeting PPARγ in lung cancer treatments.

Figure 1

Effector pathways for PPARγ in NSCLC. Antitumorigenic effects of PPARγ on NSCLC cells (top half, shaded): PPARγ-mediated suppression of COX-2 expression in NSCLC leads to decreased PGE₂ production, which inhibits NSCLC proliferation. PPARγ can also increase expression and enzymatic activity of PTEN. This leads to inhibition of Akt activation (pAkt), and subsequent decreased activity of the transcription factor NF-κB. NF-κB is a transcription factor that is critical for the production of proangiogenic and proinflammatory cytokines, such as IL-6, IL-8 and VEGF. Decreased production of these factors would be expected to block tumor angiogenesis. PPARγ-mediated suppression of members of the Snail family of transcription factors, such as Snail, Zeb, or Twist, would lead to derepression of E-cadherin expression and promote the epithelial phenotype, leading to decreased migration and invasiveness. Protumorigenic effects of PPARγ on NSCLC cells (bottom half): TGFβ-induced PPARγ has been shown to bind to Smad3 and p-Smad3, which decreases nuclear accumulation of p-Smad3 and leads to TGFβ resistance of H460 NSCLC cells. MKK4 depletion in lung cancer cells leads to increased expression of PPARγ and activation of a PPARγ-dependent transcriptional program. Depletion of PPARγ by shRNA in MKK4-depleted lung cancer cells has been shown to reduce invasion in vitro.

Figure 2

The role of PPARγ signaling in the tumor microenvironment. Activation of PPARγ in macrophages promotes a tumor-associated phenotype, which leads to increased tumor angiogenesis, matrix breakdown, and tumor cell motility. Activation of PPARγ in myeloid cells promotes lung cancer progression and metastasis in mice. Similarly, activation of PPARγ in the tumor microenvironment leads to generation of Tregs and inhibition of host T-cell antitumor activity, resulting in an immunosuppressive environment that promotes tumor progression. TZDs have been shown to inhibit angiogenesis by decreasing endothelial cell proliferation and migration, inducing endothelial cell apoptosis, and by decreasing VEGF production. However, activation of PPARγ by 15d-PGJ2 has been shown to upregulate VEGF expression in human breast cancer cells, which may contribute to increased tumor angiogenesis. Finally, PPARγ expression has been shown to be upregulated in stromal myofibroblasts surrounding colon adenocarcinomas, which promote proliferation, mobility, and invasion of tumor cells.