Fig. 2.

Regulatory functions of anti-cancer WNTs by activating the noncanonical WNT pathways in NSCLC. A WNT5a and WNT11 bind to FZDs and G protein subunit to recruit DVL, which triggers PLC activity and promotes intracellular Ca²⁺ release, and further activates calcium-dependent PKC and CAMKII signaling pathways, thus to regulate the expression of downstream genes to promote the proliferation and invasion of NSCLC cells by inducing the accumulation of nuclear NFAT transcription factors. WNT5a also inhibits VEGF-A-induced endothelial cell migration and motility to promote angiogenesis by inducing miR-27b and direct consequence of PPARγ reduction in NSCLC cells. Smoke and ATF-2 could activate the noncanonical WNT pathway by up-regulating the expression of WNT5a and WNT11. B The β-catenin-independent Wnt/PCP/JNK pathway is initiated by the cumulative binding of WNT7a to the ROR1/2-FZDs complex, then DVL is activated to bind to some small Rho GTPases such as RAC1 and RhoA to trigger JNK. This results in the inhibition of transformed cell growth but enhancement of migration and invasion of NSCLC cells. The binding of WNT7a to FZD9 inhibits cellular transformation and proliferation of NSCLC cells by activating the tumor suppressor PPARγ via the ERK5-dependent pathway, thus to relieve the inhibitory effect of MDM2 on p53 tumor suppressor pathway by inducing the expression of anti-cancer miR-29b, and promotes epithelial differentiation through activating JNK pathway and the resultant upregulation of cadherins. Wnt7a also triggers the cellular senescence of lung cancer via the inactivation of Skp2, a key negative regulator of cellular senescence. CAMKII calmodulin-dependent protein kinase II, DVL disheveled, ERK5 extracellular signal-regulated kinase 5, JNK JUN N-terminal kinase, MDM2 murine double minute 2, NFAT nuclear factor of activated T cells, NSCLC non-small cell lung cancer, PCP planar cell polarity, PKC protein kinase C, PLC phospholipase C, PPARγ peroxisome proliferator–activated receptor-γ, RAC1 Rac family small GTPase 1, ROR1/2 receptor tyrosine kinase-like orphan receptor 1/2, Skp2 S-phase kinase-associated protein-2, VEGF-A vascular endothelial growth factor-A