Anticancer actions of PPARγ ligands: Current state and future perspectives in human lung cancer

Table 1 PPARγ-dependent signals mediate the effects of PPARγ ligands in lung cancer cells

PPARγ ligands inhibit cancer cell growth and induce apoptosis via:

↓PGE2 receptors (e.g. EP2 and EP4)

↑Tumor suppressors (e.g. PTEN, p21, AP-2α, p53)

↓Inflammatory factors (e.g. NF-κB, MCP-1, COX-2)

↓Angiogenic factor (e.g. VEGF)

↓Survival factors (e.g. SAPK/JNK, ILK, Src, FAK, PI3-K/Akt, mTOR)

↑↓Other kinase signals (e.g. ERK, p38 MAPK)

↓Growth factor receptors (e.g. EGF-R, PDGF-R)

↓Extracellular matrices (e.g. Fibronectin, MMP-2, MMP-9)

↓Integrin receptors (e.g. α5β1)

↑↓Others [e.g. cytokines (e.g. IL-13, IL-21, TGF-β1) and chemokines (e.g. MIP-1β)]

↓Bcl-1, c-IAP2, etc.

PPARγ ligands stimulate cancer cell growth and reduce apoptosis via:

↑Wnt signaling and oncogenes (e.g. cyclin D1, β-catenin, c-Myc)

↑Angiogenic signaling (e.g. VEGF, Angptl4)

PPAR: Peroxisome proliferator-activated receptor; SAPK/JNK: Stress-activated protein kinase/c-Jun NH2-terminal kinase; ILK: Integrin-linked kinase; PI3-K: Phosphatidylinositol 3-kinase; ERK: Extracellular signal-regulated kinase; mTOR: Mammalian target of rapamycin; NF-κB: Nuclear factor-κB; VEGF: Vascular endothelial growth factor; IL: Interleukin; TGF: Transforming growth factor; COX: Cyclooxygenase; MCP-1: Monocyte chemotactic protein-1.

Table 2 PPARγ-independent signals triggered by PPARγ ligands in lung cancer cells

↑Tumor suppressors (e.g. LKB1, AMPK, TSC2)

↑ROS production and ERK, SAPK/JNK, p38 MAPK activation (note

that this also occurs in PPARγ-dependent pathways)

↓Effects on transcription factors (e.g. AP-1, NF-κB, Smads, Sp1, CRE)

↓Nicotine receptor signaling (e.g. α4 and α7 nAChRs)

↓Apoptosis-related signals (e.g. Bcl-2, cyclin D1, c-FLIP, DR-5)

↑Apoptosis-related signals (e.g. casease 3/7, cyclin D1, p53)

AMPK: AMP-activated protein kinase (AMPK); TSC2: Tuberous sclerosis complex 2.