Prostacyclin Inhibits Non-Small Cell Lung Cancer Growth by a Frizzled 9-Dependent Pathway That Is Blocked by Secreted Frizzled-Related Protein 1

Abstract

The goal of this study was to assess the ability of iloprost, an orally active prostacyclin analog, to inhibit transformed growth of human non-small cell lung cancer (NSCLC) and to define the mechanism of iloprost's tumor suppressive effects. In a panel of NSCLC cell lines, the ability of iloprost to inhibit transformed cell growth was not correlated with the expression of the cell surface receptor for prostacyclin, but instead was correlated with the presence of Frizzled 9 (Fzd 9) and the activation of peroxisome proliferator-activated receptor-gamma (PPARgamma). Silencing of Fzd 9 blocked PPARgamma activation by iloprost, and expression of Fzd 9 in cells lacking the protein resulted in iloprost's activation of PPARgamma and inhibition of transformed growth. Interestingly, soluble Frizzled-related protein-1, a well-known inhibitor of Wnt/Fzd signaling, also blocked the effects of iloprost and Fzd 9. Moreover, mice treated with iloprost had reduced lung tumors and increased Fzd 9 expression. These studies define a novel paradigm, linking the eicosanoid pathway and Wnt signaling. In addition, these data also suggest that prostacyclin analogs may represent a new class of therapeutic agents in the treatment of NSCLC where the restoration of noncanonical Wnt signaling maybe important for the inhibition of transformed cell growth.

hsa-miR29b, a critical downstream target of non-canonical Wnt signaling, plays an anti-proliferative role in non-small cell lung cancer cells via targeting MDM2 expression

“…Stimulation of NSCLC cells with Wnt7a not only induced the expression of hsa-miR29b but also attenuated NSCLC cell proliferation (Tennis et al, 2010; Winn et al, 2005). To test if the anti-proliferative effects of Wnt7a in NSCLC cells are mediated via the induction of hsa-miR29b, we first stimulated A549 cells with Wnt7a (to induce hsa-miR29b expression), followed by treatment with miR29b precursors.…”

Non-small-cell lung cancer: molecular targeted therapy and personalized medicine – drug resistance, mechanisms, and strategies

“…Interestingly, it has been shown that a PGI 2 analogue125 can mimic many of the effects of Wnt 7a in the context of Frizzled 9. Recent studies have also shown that the addition of prostacyclin to lung cancer cell lines that have retained Wnt 7a receptor Frizzled 9 results in decreased proliferation, inhibition of anchorage-independent growth,126 and significantly decreases lung cancer growth in vitro.123,126…”

Cyclooxygenases and lipoxygenases in cancer

“…By preventing platelet aggregation, PGI 2 might also reduce the amount of plateletsecreted VEGF and unwanted angiogenesis [31]. In addition to these platelet-mediated effects, it has been recently shown that PGI 2 can prevent non-small cell lung cancer growth by enhancing frizzled-9 expression and activation of the peroxisome proliferator-activated receptor (PPAR)gamma [32, 33]. Interestingly, this novel PGI 2 /frizzled-9 crosstalk does not correlate with the expression of the cell surface receptor for PGI 2 , suggesting that PGI 2 might exert an anti-tumorigenic activity in a receptor-independent manner.…”