{"doi":"10.1016/j.jbc.2022.102479","title":"Pyrvinium doubles against WNT-driven cancer","abstract":"The WNT–β-catenin signaling pathway has a major role in regulating cell proliferation and differentiation. Aberrant activation of the pathway contributes to various human cancer types. Because casein kinase CK1α-initiated phosphorylation of β-catenin is a key first step to restrain WNT signaling, effective restoration of CK1α activity represents an innovative strategy to combat WNT-driven cancer. A recent study in JBC reveals the anthelmintic pyrvinium directly binds to CK1α as an activator and also stabilizes CK1α protein, doubling against WNT-driven cancer activity. The WNT–β-catenin signaling pathway has a major role in regulating cell proliferation and differentiation. Aberrant activation of the pathway contributes to various human cancer types. Because casein kinase CK1α-initiated phosphorylation of β-catenin is a key first step to restrain WNT signaling, effective restoration of CK1α activity represents an innovative strategy to combat WNT-driven cancer. A recent study in JBC reveals the anthelmintic pyrvinium directly binds to CK1α as an activator and also stabilizes CK1α protein, doubling against WNT-driven cancer activity. The Casein kinase 1α agonist pyrvinium attenuates Wnt-mediated CK1α degradation via interaction with the E3 ubiquitin ligase component CereblonJournal of Biological ChemistryVol. 298Issue 8PreviewThe Cullin-RING ligase 4 E3 ubiquitin ligase component Cereblon (CRBN) is a well-established target for a class of small molecules termed immunomodulatory drugs (IMiDs). These drugs drive CRBN to modulate the degradation of a number of neosubstrates required for the growth of multiple cancers. Whereas the mechanism underlying the activation of CRBN by IMiDs is well described, the normal physiological regulation of CRBN is poorly understood. We recently showed that CRBN is activated following exposure to Wnt ligands and subsequently mediates the degradation of a subset of physiological substrates. Full-Text PDF Open Access Since the first Wnt gene discovery about 40 years ago, evolutionarily conserved Wnt signaling has attracted tremendous attention due to its essential roles in regulating embryonic development and governing stem cell proliferation and differentiation (1Logan C.Y. Nusse R. The Wnt signaling pathway in development and disease.Annu. Rev. Cell Dev. Biol. 2004; 20: 781-810Crossref PubMed Scopus (4319) Google Scholar). The signaling pathway is activated by a family of 19 lipoglycoproteins called WNTs in humans, whose production, secretion, and diffusion through tissues are tightly regulated. Depending on the ligand-receptor combination, cellular context, and downstream events regulated, Wnt signaling is transmitted through two overlapping but distinct pathways: the β-catenin–independent pathway (i.e., noncanonical pathway) and the β-catenin–dependent pathway (canonical pathway). While less understood, the noncanonical pathway is involved in cytoskeleton rearrangement, cell polarity, and migration (also known as WNT/planar cell polarity or WNT/PCP branch) or in promoting proliferation and antagonizing the canonical pathway through the WNT/Ca2+ branch. On the other hand, strongly associated with human diseases and cancer, the canonical pathway has been the focus of most WNT-related studies. In this pathway, WNT binds to one of 10 Frizzled (FZD) receptors and the coreceptors LDL-receptor–related proteins 5 and 6 (LRP5 and LRP6), transduces the signal through the FZD-associated scaffolding protein Dishevelled (DVL), and recruits binding protein AXIN to the cytoplasm membrane, leading to the release of β-catenin from the dissembled destruction complex containing AXIN, adenomatous polyposis coli (APC), glycogen synthase kinase 3β, casein kinase 1α (CK1α), the E3-ubiquitin ligase β-TrCP, and protein phosphatase 2A (2MacDonald B.T. Tamai K. He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases.Dev. Cell. 2009; 17: 9-26Abstract Full Text Full Text PDF PubMed Scopus (4351) Google Scholar).","journal":"Journal of Biological Chemistry","year":2022,"id":275688,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9475,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":265793,"name":"Russell R. Reid","orcid":"0000-0002-1111-4500","position":1,"is_corresponding":false},{"id":265798,"name":"Tong‐Chuan He","orcid":"0000-0001-7721-3934","position":2,"is_corresponding":false},{"id":511586,"name":"Jiaming Fan","orcid":"0000-0001-8523-4188","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-19T00:28:21.971703Z","pmid":"36096200","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}