Antitumorigenic Effect of Wnt 7a and Fzd 9 in Non-small Cell Lung Cancer Cells Is Mediated through ERK-5-dependent Activation of Peroxisome Proliferator-activated Receptor γ

Abstract

The Wnt pathway is critical for normal development, and mutation of specific components is seen in carcinomas of diverse origins. The role of this pathway in lung tumorigenesis has not been clearly established. Recent studies from our laboratory indicate that combined expression of the combination of Wnt 7a and Frizzled 9 (Fzd 9) in Non-small Cell Lung Cancer (NSCLC) cell lines inhibits transformed growth. We have also shown that increased expression of peroxisome proliferator-activated receptor ␥ (PPAR␥) inhibits transformed growth of NSCLC and promotes epithelial differentiation of these cells. The goal of this study was to determine whether the effects of Wnt 7a/Fzd 9 were mediated through PPAR␥. We found that Wnt 7a and Fzd 9 expression led to increased PPAR␥ activity. This effect was not mediated by altered expression of the protein. Wnt 7a and Fzd 9 expression resulted in activation of ERK5, which was required for PPAR␥ activation in NSCLC. SR 202, a known PPAR␥ inhibitor, blocked the increase in PPAR␥ activity and restored anchorage-independent growth in NSCLC expressing Wnt 7a and Fzd 9. SR 202 also reversed the increase in E-cadherin expression mediated by Wnt 7a and Fzd 9. These data suggest that ERK5-dependent activation of PPAR␥ represents a major effector pathway mediating the anti-tumorigenic effects of Wnt 7a and Fzd 9 in NSCLC.Wnts are a family of secreted glycoproteins that serve as extracellular signaling molecules controlling diverse morphogenic and developmental programs (1). Signaling is mediated by a family of distinct seven-membrane receptors known as Frizzled (Fzd) 2 (2), and is further regulated by co-receptors LRP 5/6 (3). Aberrant Wnt signaling has been implicated in a variety of cancers (4, 5). Our laboratory has focused on the role of Wnt signaling in lung cancer. We have previously reported that the restoration of Wnt 7a and Fzd 9 signaling inhibited both cell proliferation and anchorage-independent growth, promoted cellular differentiation, and reversed the transformed phenotype in Non-small Cell Lung Cancer cells (NSCLC) (6). These findings unveil a novel tumor suppressor pathway in lung cancer and implicate Wnt 7a and Fzd 9 in the maintenance of epithelial cellular differentiation. The downstream effector pathways mediating these effects are not well understood. Proliferator-activated receptor ␥ (PPAR␥) is a member of the PPAR family of ligand-activated nuclear receptors implicated in a wide variety of biological functions (7). Three PPAR isoforms have been identified, ␣, ␥, and ␤/␦, which all bind as heterodimers with the retinoic acid X receptor to specific regulatory elements in the promoter regions of their target genes. The role of PPAR␥ has been extensively studied in a variety of cancers including colon, breast, prostate, and lung (see Ref. 8 for review). Inactivating mutations in the PPAR␥ gene have been seen in colon cancers (9, 10), suggesting that PPAR␥ behaves as a tumor suppressor gene. Pharmacological activators of PPAR␥ inhibit growth of NSCLC cells and induce ap...

Prognostic role of Wnt7a expression in ovarian carcinoma patients

“…In nonsmall cell lung carcinoma, Wnt7a was reported to function as a tumor suppressor gene. The anti-tumorgenic effects of Wnt7a interacting with the specific receptor Fzd9 was mainly mediated through ERK-dependent activation of the nuclear receptor gene PPARγ [15]. On the other hand, Wnt7a positively regulated E-cadherin in lung carcinoma cell.…”

“…Wnt7a was overexpressed in the cell lines of colorectal carcinoma, pancreatic carcinoma, gastric carcinoma and breast carcinoma [14]. However, Wnt7a has been reported to function as a tumor suppressor gene in non-small cell lung carcinoma [15]. In addition, the Wnt7a gene was also found to be down-regulated because of hypermethylation at high frequency in pancreatic carcinoma [16].…”

Wnt-5a/Frizzled9 Receptor Signaling through the Gαo-Gβγ Complex Regulates Dendritic Spine Formation

“…Together, these data strongly suggest that FZD9 is located in the postsynaptic region of hippocampal neurons. (32)(33)(34). To assess whether FZD9 might also mediates the Wnt-5a cascade, we first performed a ligandreceptor binding assay between recombinant Wnt-5a and the cysteine-rich domain (CRD) of FZD9, which is a Wnt-binding domain (35).…”

Mitogen/Extracellular Signal-Regulated Kinase Kinase-5 Promoter Region Polymorphisms Affect the Risk of Sporadic Colorectal Cancer in a Southern Chinese Population

“…Ghosh et al (2005) showed that exogenous expression of c-myc promoter-binding protein 1 induces prostate cancer cell death by downregulating the expression of MEK5a and upregulating the level of MEK5b. There are also some studies indicating that MEK5 plays an important role in the carcinogenesis of hepatocellular cancer (Yan et al, 2009) and lung cancer (Winn et al, 2006). However, few studies have investigated the role of MEK5 in sporadic CRC.…”

“…Further, it is thought that MEK5 is directly involved in the progress of malignancies and tumorigenesis (Song et al, 2004). There are many studies suggesting that MEK5 plays a critical role in cancer occurrence and progression, such as prostate cancer (Mehta et al, 2003;McCracken et al, 2008), breast cancer (Li et al, 2008), hepatocellular cancer (Yan et al, 2009), and lung cancer (Winn et al, 2006). However, the association between MEK5 and CRC remains unclear.…”