Dataset Information

Differential abundance of CK1? provides selectivity for pharmacological CK1? activators to target WNT-dependent tumors.

ABSTRACT: Constitutive WNT activity drives the growth of various human tumors, including nearly all colorectal cancers (CRCs). Despite this prominence in cancer, no WNT inhibitor is currently approved for use in the clinic largely due to the small number of druggable signaling components in the WNT pathway and the substantial toxicity to normal gastrointestinal tissue. We have shown that pyrvinium, which activates casein kinase 1? (CK1?), is a potent inhibitor of WNT signaling. However, its poor bioavailability limited the ability to test this first-in-class WNT inhibitor in vivo. We characterized a novel small-molecule CK1? activator called SSTC3, which has better pharmacokinetic properties than pyrvinium, and found that it inhibited the growth of CRC xenografts in mice. SSTC3 also attenuated the growth of a patient-derived metastatic CRC xenograft, for which few therapies exist. SSTC3 exhibited minimal gastrointestinal toxicity compared to other classes of WNT inhibitors. Consistent with this observation, we showed that the abundance of the SSTC3 target, CK1?, was decreased in WNT-driven tumors relative to normal gastrointestinal tissue, and knocking down CK1? increased cellular sensitivity to SSTC3. Thus, we propose that distinct CK1? abundance provides an enhanced therapeutic index for pharmacological CK1? activators to target WNT-driven tumors.

SUBMITTER: Li B

PROVIDER: S-EPMC5555225 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors.

Li Bin B Orton Darren D Neitzel Leif R LR Astudillo Luisana L Shen Chen C Long Jun J Chen Xi X Kirkbride Kellye C KC Doundoulakis Thomas T Guerra Marcy L ML Zaias Julia J Fei Dennis Liang DL Rodriguez-Blanco Jezabel J Thorne Curtis C Wang Zhiqiang Z Jin Ke K Nguyen Dao M DM Sands Laurence R LR Marchetti Floriano F Abreu Maria T MT Cobb Melanie H MH Capobianco Anthony J AJ Lee Ethan E Robbins David J DJ

Science signaling 20170627 485

Constitutive WNT activity drives the growth of various human tumors, including nearly all colorectal cancers (CRCs). Despite this prominence in cancer, no WNT inhibitor is currently approved for use in the clinic largely due to the small number of druggable signaling components in the WNT pathway and the substantial toxicity to normal gastrointestinal tissue. We have shown that pyrvinium, which activates casein kinase 1α (CK1α), is a potent inhibitor of WNT signaling. However, its poor bioavaila ...[more]

PMID: 28655862

Similar Datasets

Project description:AimsPhenformin, resveratrol and AICAR stimulate the energy sensor 5'-AMP activated kinase (AMPK) and inhibit the first step of ribosome biogenesis, de novo RNA synthesis in nucleoli. Nucleolar activities are relevant to human health, because ribosome production is crucial to the development of diabetic complications. Although the function of nucleoli relies on their organization, the impact of AMPK activators on nucleolar structures is not known. Here, we addressed this question by examining four nucleolar proteins that are essential for ribosome biogenesis.MethodsKidney cells were selected as model system, because diabetic nephropathy is one of the complications associated with diabetes mellitus. To determine the impact of pharmacological agents on nucleoli, we focused on the subcellular and subnuclear distribution of B23/nucleophosmin, fibrillarin, nucleolin and RPA194. This was achieved by quantitative confocal microscopy at the single-cell level in combination with cell fractionation and quantitative Western blotting.ResultsAMPK activators induced the re-organization of nucleoli, which was accompanied by changes in cell proliferation. Among the compounds tested, phenformin and resveratrol had the most pronounced impact on nucleolar organization. For B23, fibrillarin, nucleolin and RPA194, both agents (i) altered the nucleocytoplasmic distribution and nucleolar association and (ii) reduced significantly the retention in the nucleus. (iii) Phenformin and resveratrol also increased significantly the total concentration of B23 and nucleolin.ConclusionsAMPK activators have unique effects on the subcellular localization, nuclear retention and abundance of nucleolar proteins. We propose that the combination of these events inhibits de novo ribosomal RNA synthesis and modulates cell proliferation. Our studies identified nucleolin as a target that is especially sensitive to pharmacological AMPK activators. Because of its response to pharmacological agents, nucleolin represents a potential biomarker for the development of drugs that diminish diabetic renal hypertrophy.

Dataset Information

Differential abundance of CK1? provides selectivity for pharmacological CK1? activators to target WNT-dependent tumors.

Publications

Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets