Inhibition of the Wnt palmitoyltransferase porcupine suppresses cell growth and downregulates the Wnt/β-catenin pathway in gastric cancer

Abstract

Similarly to the Wnt protein palmitoyltransferase, porcupine (PPN) is essential to the activation of the Wnt/β-catenin signaling pathway. However, little is known about the role of PPN activity in human gastric cancer, one of the most common causes of cancer-related mortality. Real-time quantitative PCR was used to detect the expression levels of PPN in paired gastric cancer tissues. Cell proliferation, migration and invasion assays were performed following treatment using a newly developed small molecule PPN inhibitor (inhibitors of Wnt production, IWP-2) in the gastric cancer MKN28 cell line. Expression of downstream target genes and transcriptional activity of the Wnt/β-catenin signaling pathway were examined following IWP-2 treatment in MKN28. We identified that PPN was overexpressed in human gastric cancer tissue samples and cell lines. Following treatment of the gastric cancer cell line MKN28 with IWP-2, we detected that IWP-2 decreased MKN28 cell proliferation, migration and invasion, and elevated caspase 3/7 activity. Further analysis demonstrated that IWP-2 downregulated the transcriptional activity of the Wnt/β-catenin signaling pathway and downregulated the expression levels of downstream Wnt/β-catenin target genes in MKN28 cells. As current Wnt pathway-targeting strategies used for anticancer therapy have mainly focused on Wnt-receiving cells, our data shed light on the potential use of Wnt palmitoyltransferase PPN inhibitors to abrogate Wnt production in Wnt-producing cells, thus providing a potential therapeutic option for gastric cancer.

WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited

“…To confirm that these findings are translatable into a pathophysiological model of CC in vivo, we gave the CTNNB1-CTBP inhibitor ICG-001 to rats treated with TAA for 26 weeks. Furthermore, as we hypothesize that CC is still dependent on WNT ligand due to relatively infrequent mutations in Apc or Ctnnb1, we inhibited WNT ligand secretion using the small molecule C-59, as this compound also inhibited human CC growth in vitro and in xenografts (2,53,55,56). We administered ICG-001, C-59, or vehicle alone once tumors had established at week 21, through to week 26, during which tumors normally undergo rapid growth ( Figure 8A).…”

“…These mutations per se lead to insensitivity to inhibitors targeting the WNT ligand or the receptors (1). This class of drugs, which includes inhibitors of porcupine in order to inhibit WNT secretion and LRP6 to block cell surface signaling, are the best-characterized WNT inhibitors (2). An increasingly diverse collection of small molecules against the WNT pathway are being trialed clinically (3).…”

Interaction between Wnt/β-catenin pathway and microRNAs regulates epithelial-mesenchymal transition in gastric cancer (Review)

“…Interestingly, ANLN manifested higher expression among proliferative type gastric tumors compared to invasive or metabolic types (74). Overexpression of cadherin-17 (CDH17), frizzled (FzE3), Yin Yang 1 (YY1), porcupine (PPN) has all been discovered to account for Wnt motivation, together with cell growth in gastric cancer (75)(76)(77)(78).…”

Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review

“…Certain cancer cells that express caveolins are more aggressive and metastatic, as well as drug-resistant [77] . The upregulation of Fzd-3, Wnt palmitoyltransferase porcupine (PPN), and CDH17 has been found to be critical for cell proliferation and activation of the Wnt/ b-catenin signaling pathway in gastric cancer [78][79][80] . Moreover, Lu et al [81] have provided evidence indicating that EZH2 (histone methyl-transferase, enhancer of zeste homolog 2) activates Wnt signaling in gastric cancer mainly by downregulating the expression of CXXC4 (CXXC finger protein 4) without involving DNA methylation.…”

“…Homeostasis of the gastrointestinal epithelium is 87 [47,[69][70][71][72][73][74][75]232] Fzd-3 [78] CTNNB1 [9,[88][89][90][91][92][93]96,97] LRP6 [228] TCF7L2 [98][99][100] PPN [79] CDH17 [80] EZH2 [81] HMGA1, HMGA2 [210,211] YY1 [86] TC1 (C8orf4) [201,202] miR-17-92 [161] mir-10a [168] has-miR-335 [166] hsa-miR-375 [163] Downregulation or function inhibition in gastric cancer Downregulation by hypermethylation Inactivation by miRNAs APC [145,146] APC [175] sFRP1, sFRP2, sFRP4, sFRP5 [78,96,149] AXIN2 [159] WIF-1 [144,149] EZF1 [78] Dkk-1, Dkk-2, Dkk-3 [59,144,148,…”