The use of porcupine inhibitors to target Wnt-driven cancers
01 Dec 2015-Bioorganic & Medicinal Chemistry Letters (Bioorg Med Chem Lett)-Vol. 25, Iss: 23, pp 5472-5476
TL;DR: This review shall provide an overview of the reported small molecule inhibitors for PORCN and discuss the progress made in identifying human disease models that are responsive to POR CN inhibitors.
About: This article is published in Bioorganic & Medicinal Chemistry Letters.The article was published on 2015-12-01. It has received 43 citations till now. The article focuses on the topics: PORCN & Wnt signaling pathway.
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TL;DR: The role of Wnt/β-catenin pathway in cancer and ongoing therapeutic strategies involving this pathway are summarized to highlight its potential impact on responses to immunotherapy treatments.
Abstract: Wnt/β-catenin signaling, a highly conserved pathway through evolution, regulates key cellular functions including proliferation, differentiation, migration, genetic stability, apoptosis, and stem cell renewal. The Wnt pathway mediates biological processes by a canonical or noncanonical pathway, depending on the involvement of β-catenin in signal transduction. β-catenin is a core component of the cadherin protein complex, whose stabilization is essential for the activation of Wnt/β-catenin signaling. As multiple aberrations in this pathway occur in numerous cancers, WNT-directed therapy represents an area of significant developmental therapeutics focus. The recently described role of Wnt/β-catenin pathway in regulating immune cell infiltration of the tumor microenvironment renewed the interest, given its potential impact on responses to immunotherapy treatments. This article summarizes the role of Wnt/β-catenin pathway in cancer and ongoing therapeutic strategies involving this pathway.
407 citations
Cites background from "The use of porcupine inhibitors to ..."
...Membrane bound O-acyl transferase porcupine (PORCN) has emerged as a molecular target of interest to treat WNT-driven cancers [56]....
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TL;DR: This review is an attempt to highlight the latest developments in the understanding of Wnt signaling in the context of tumors and their microenvironment and summarized the ongoing strategies used to target aberrant WNT signaling as a novel therapeutic intervention to combat various cancers.
Abstract: Wnt signaling is one of the central mechanisms regulating tissue morphogenesis during embryogenesis and repair. The pivot of this signaling cascade is the Wnt ligand, which binds to receptors belonging to the Frizzled family or the ROR1/ROR2 and RYK family. This interaction governs the downstream signaling cascade (canonical/non-canonical), ultimately extending its effect on the cellular cytoskeleton, transcriptional control of proliferation and differentiation, and organelle dynamics. Anomalous Wnt signaling has been associated with several cancers, the most prominent ones being colorectal, breast, lung, oral, cervical, and hematopoietic malignancies. It extends its effect on tumorigenesis by modulating the tumor microenvironment via fine crosstalk between transformed cells and infiltrating immune cells, such as leukocytes. This review is an attempt to highlight the latest developments in the understanding of Wnt signaling in the context of tumors and their microenvironment. A dynamic process known as immunoediting governs the fate of tumor progression based on the correlation of various signaling pathways in the tumor microenvironment and immune cells. Cancer cells also undergo a series of mutations in the tumor suppressor gene, which favors tumorigenesis. Wnt signaling, and its crosstalk with various immune cells, has both negative as well as positive effects on tumor progression. On one hand, it helps in the maintenance and renewal of the leucocytes. On the other hand, it promotes immune tolerance, limiting the antitumor response. Wnt signaling also plays a role in epithelial-mesenchymal transition (EMT), thereby promoting the maintenance of Cancer Stem Cells (CSCs). Furthermore, we have summarized the ongoing strategies used to target aberrant Wnt signaling as a novel therapeutic intervention to combat various cancers and their limitations.
139 citations
Cites background from "The use of porcupine inhibitors to ..."
...It recently became a highly druggable target for inhibiting Wnt signaling pathways (97, 98)....
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TL;DR: This pathway should be a main target in cancer therapy as WNT signaling activation is essential for tumor progression and survival, even in the presence of the anti-tumoral immune response and/or antineoplastic drugs.
Abstract: WNT/β-catenin signaling is involved in many physiological processes. Its implication in embryonic development, cell migration, and polarization has been shown. Nevertheless, alterations in this signaling have also been related with pathological events such as sustaining and proliferating the cancer stem cell (CSC) subset present in the tumor bulk. Related with this, WNT signaling has been associated with the maintenance, expansion, and epithelial-mesenchymal transition of stem cells, and furthermore with two distinctive features of this tumor population: therapeutic resistance (MDR, multidrug resistance) and immune escape. These mechanisms are developed and maintained by WNT activation through the transcriptional control of the genes involved in such processes. This review focuses on the description of the best known WNT pathways and the molecules involved in them. Special attention is given to the WNT cascade proteins deregulated in tumors, which have a decisive role in tumor survival. Some of these proteins function as extrusion pumps that, in the course of chemotherapy, expel the drugs from the cells; others help the tumoral cells hide from the immune effector mechanisms. Among the WNT targets involved in drug resistance, the drug extrusion pump MDR-1 (P-GP, ABCB1) and the cell adhesion molecules from the CD44 family are highlighted. The chemokine CCL4 and the immune checkpoint proteins CD47 and PD-L1 are included in the list of WNT target molecules with a role in immunity escape. This pathway should be a main target in cancer therapy as WNT signaling activation is essential for tumor progression and survival, even in the presence of the anti-tumoral immune response and/or antineoplastic drugs. The appropriate design and combination of anti-tumoral strategies, based on the modulation of WNT mediators and/or protein targets, could negatively affect the growth of tumoral cells, improving the efficacy of these types of therapies.
136 citations
Cites background from "The use of porcupine inhibitors to ..."
...Additionally, specific inhibitors have been found that neutralize Porcupine, preventing acylation, and WNT secretion (179)....
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TL;DR: Wang et al. as mentioned in this paper reviewed the most updated knowledge of Wnt/β-catenin signaling in cancers and relatively targeted therapies to generate a clearer and more accurate awareness of both the developmental stage and underlying limitations of WNT/α-Catenin-targeted therapies in cancers.
Abstract: Wnt/β-catenin signaling has been broadly implicated in human cancers and experimental cancer models of animals. Aberrant activation of Wnt/β-catenin signaling is tightly linked with the increment of prevalence, advancement of malignant progression, development of poor prognostics, and even ascendence of the cancer-associated mortality. Early experimental investigations have proposed the theoretical potential that efficient repression of this signaling might provide promising therapeutic choices in managing various types of cancers. Up to date, many therapies targeting Wnt/β-catenin signaling in cancers have been developed, which is assumed to endow clinicians with new opportunities of developing more satisfactory and precise remedies for cancer patients with aberrant Wnt/β-catenin signaling. However, current facts indicate that the clinical translations of Wnt/β-catenin signaling-dependent targeted therapies have faced un-neglectable crises and challenges. Therefore, in this study, we systematically reviewed the most updated knowledge of Wnt/β-catenin signaling in cancers and relatively targeted therapies to generate a clearer and more accurate awareness of both the developmental stage and underlying limitations of Wnt/β-catenin-targeted therapies in cancers. Insights of this study will help readers better understand the roles of Wnt/β-catenin signaling in cancers and provide insights to acknowledge the current opportunities and challenges of targeting this signaling in cancers.
95 citations
TL;DR: Crystal structures of DltB, a bacterial membrane-bound O-acyltransferase, are reported both alone and in complex with the d-alanyl donor protein DltC, suggesting that MBOATs from different organisms have similar catalytic mechanisms.
Abstract: Membrane-bound O-acyltransferases (MBOATs) are a superfamily of integral transmembrane enzymes that are found in all kingdoms of life1. In bacteria, MBOATs modify protective cell-surface polymers. In vertebrates, some MBOAT enzymes—such as acyl-coenzyme A:cholesterol acyltransferase and diacylglycerol acyltransferase 1—are responsible for lipid biosynthesis or phospholipid remodelling2,3. Other MBOATs, including porcupine, hedgehog acyltransferase and ghrelin acyltransferase, catalyse essential lipid modifications of secreted proteins such as Wnt, hedgehog and ghrelin, respectively4–10. Although many MBOAT proteins are important drug targets, little is known about their molecular architecture and functional mechanisms. Here we present crystal structures of DltB, an MBOAT responsible for the d-alanylation of cell-wall teichoic acid in Gram-positive bacteria11–16, both alone and in complex with the d-alanyl donor protein DltC. DltB contains a ring of 11 peripheral transmembrane helices, which shield a highly conserved extracellular structural funnel extending into the middle of the lipid bilayer. The conserved catalytic histidine residue is located at the bottom of this funnel and is connected to the intracellular DltC through a narrow tunnel. Mutation of either the catalytic histidine or the DltC-binding site of DltB abolishes the d-alanylation of lipoteichoic acid and sensitizes the Gram-positive bacterium Bacillus subtilis to cell-wall stress, which suggests cross-membrane catalysis involving the tunnel. Structure-guided sequence comparison among DltB and vertebrate MBOATs reveals a conserved structural core and suggests that MBOATs from different organisms have similar catalytic mechanisms. Our structures provide a template for understanding structure–function relationships in MBOATs and for developing therapeutic MBOAT inhibitors. Crystal structures of DltB, a bacterial membrane-bound O-acyltransferase, are reported both alone and in complex with the d-alanyl donor protein DltC.
81 citations
References
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TL;DR: The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels, and that receptor-ligand specificity and feedback loops help to determine WNT signaling outputs.
Abstract: Tight control of cell-cell communication is essential for the generation of a normally patterned embryo. A critical mediator of key cell-cell signaling events during embryogenesis is the highly conserved Wnt family of secreted proteins. Recent biochemical and genetic analyses have greatly enriched our understanding of how Wnts signal, and the list of canonical Wnt signaling components has exploded. The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels. In addition, receptor-ligand specificity and feedback loops help to determine Wnt signaling outputs. Wnts are required for adult tissue maintenance, and perturbations in Wnt signaling promote both human degenerative diseases and cancer. The next few years are likely to see novel therapeutic reagents aimed at controlling Wnt signaling in order to alleviate these conditions.
5,129 citations
TL;DR: Some key aspects of Wnt/beta-catenin signaling in human diseases including congenital malformations, cancer, and osteoporosis are highlighted, and potential therapeutic implications are discussed.
4,926 citations
TL;DR: In this review, the wnt pathway will be covered from the perspective of cancer, with emphasis placed on molecular defects known to promote neoplastic transformation in humans and in animal models.
Abstract: The regulation of cell growth and survival can be subverted by a variety of genetic defects that alter transcriptional programs normally responsible for controlling cell number. High throughput analysis of these gene expression patterns should ultimately lead to the identification of minimal expression profiles that will serve as common denominators in assigning a cancer to a given category. In the course of defining the common denominators, though, we should not be too surprised to find that cancers within a single category may nevertheless exhibit seemingly disparate genetic defects. The wnt pathway has already provided an outstanding example of this. We now know of three regulatory genes in this pathway that are mutated in primary human cancers and several others that promote experimental cancers in rodents (Fig. 1). In all of these cases the common denominator is the activation of gene transcription by -catenin. The resulting gene expression profile should provide us with a signature common to those cancers carrying defects in the wnt pathway. In this review, the wnt pathway will be covered from the perspective of cancer, with emphasis placed on molecular defects known to promote neoplastic transformation in humans and in animal models.
3,277 citations
TL;DR: This work isolated active Wnt molecules, including the product of the mouse Wnt3a gene, and found the proteins to be palmitoylated on a conserved cysteine, indicating that the lipid is important for signalling.
Abstract: Wnt signalling is involved in numerous events in animal development, including the proliferation of stem cells and the specification of the neural crest. Wnt proteins are potentially important reagents in expanding specific cell types, but in contrast to other developmental signalling molecules such as hedgehog proteins and the bone morphogenetic proteins, Wnt proteins have never been isolated in an active form. Although Wnt proteins are secreted from cells, secretion is usually inefficient and previous attempts to characterize Wnt proteins have been hampered by their high degree of insolubility. Here we have isolated active Wnt molecules, including the product of the mouse Wnt3a gene. By mass spectrometry, we found the proteins to be palmitoylated on a conserved cysteine. Enzymatic removal of the palmitate or site-directed and natural mutations of the modified cysteine result in loss of activity, and indicate that the lipid is important for signalling. The purified Wnt3a protein induces self-renewal of haematopoietic stem cells, signifying its potential use in tissue engineering.
2,323 citations
TL;DR: It is reported that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth and is important for the establishment of peak bone mass.
2,210 citations