Disruption of Wnt/β-Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human Cells

Kulak, Ozlem; Chen, Hua; Holohan, Brody; Wu, Xiaofeng; He, Huawei; Borek, Dominika; Otwinowski, Zbyszek; Yamaguchi, Kiyoshi; Garofalo, L.; Ma, Zhiqiang; Wright, Woodring E.; Chen, Chuo; Zhang, Xuewu; Lum, Lawrence

doi:10.1128/mcb.00392-15

Cited by 62 publications

(54 citation statements)

References 62 publications

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“…ETC-159 inhibits Wnt secretion and activity and is highly efficient preclinically in different cancers driven by Wnt signaling and notably in R-spondin translocation colorectal cancers 135 . The tankyrase inhibitors (XAV-939 and IWR-1) stabilize axin and induce the degradation of the β-catenin 136 and may act as anti-tumor drugs also by participating in telomere shortening 137 .…”

Section: ) Wnt Inhibiting Molecules: Biologics and Clinicsmentioning

confidence: 99%

The Wnt signaling pathway in cancer

Duchartre

Kim

Kahn

2016

Critical Reviews in Oncology/Hematology

438

344

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The Wnt signaling pathway is critically involved in both the development and homeostasis of tissues via regulation of their endogenous stem cells. Aberrant Wnt signaling has been described as a key player in the initiation of and/or maintenance and development of many cancers, via affecting the behavior of Cancer Stem Cells (CSCs). CSCs are considered by most to be responsible for establishment of the tumor and also for disease relapse, as they possess inherent drug-resistance properties. The development of new therapeutic compounds targeting the Wnt signaling pathway promises new hope to eliminate CSCs and achieve cancer eradication. However, a major challenge resides in developing a strategy efficient enough to target the dysregulated Wnt pathway in CSCs, while being safe enough to not damage the normal somatic stem cell population required for tissue homeostasis and repair. Here we review recent therapeutic approaches to target the Wnt pathway and their clinical applications.

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Section: ) Wnt Inhibiting Molecules: Biologics and Clinicsmentioning

confidence: 99%

The Wnt signaling pathway in cancer

Duchartre

Kim

Kahn

2016

Critical Reviews in Oncology/Hematology

438

344

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“…Tankyrases promote degradation of AXIN1 and AXIN2 through poly-ADP-ribosylation, and tankyrase inhibitors induce AXIN stabilization for canonical WNT/β-catenin signaling inhibition (236–238). AZ1366 (239), G007-LK (240), NVP-TNKS656 (241,242) and XAV939 (243,244) are investigational tankyrase inhibitors that can block canonical WNT/β-catenin signaling in model animal experiments to repress tumorigenesis (239–244), control neuropathic pain (245) and promote cardiac reprogramming from cardiac fibroblasts (24).…”

Section: Therapeutics Targeting Wnt Signaling Cascadesmentioning

confidence: 99%

Molecular genetics and targeted therapy of WNT-related human diseases (Review)

Katoh¹,

2017

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Canonical WNT signaling through Frizzled and LRP5/6 receptors is transduced to the WNT/β-catenin and WNT/stabilization of proteins (STOP) signaling cascades to regulate cell fate and proliferation, whereas non-canonical WNT signaling through Frizzled or ROR receptors is transduced to the WNT/planar cell polarity (PCP), WNT/G protein-coupled receptor (GPCR) and WNT/receptor tyrosine kinase (RTK) signaling cascades to regulate cytoskeletal dynamics and directional cell movement. WNT/β-catenin signaling cascade crosstalks with RTK/SRK and GPCR-cAMP-PKA signaling cascades to regulate β-catenin phosphorylation and β-catenin-dependent transcription. Germline mutations in WNT signaling molecules cause hereditary colorectal cancer, bone diseases, exudative vitreoretinopathy, intellectual disability syndrome and PCP-related diseases. APC or CTNNB1 mutations in colorectal, endometrial and prostate cancers activate the WNT/β-catenin signaling cascade. RNF43, ZNRF3, RSPO2 or RSPO3 alterations in breast, colorectal, gastric, pancreatic and other cancers activate the WNT/β-catenin, WNT/STOP and other WNT signaling cascades. ROR1 upregulation in B-cell leukemia and solid tumors and ROR2 upregulation in melanoma induce invasion, metastasis and therapeutic resistance through Rho-ROCK, Rac-JNK, PI3K-AKT and YAP signaling activation. WNT signaling in cancer, stromal and immune cells dynamically orchestrate immune evasion and antitumor immunity in a cell context-dependent manner. Porcupine (PORCN), RSPO3, WNT2B, FZD5, FZD10, ROR1, tankyrase and β-catenin are targets of anti-WNT signaling therapy, and ETC-159, LGK974, OMP-18R5 (vantictumab), OMP-54F28 (ipafricept), OMP-131R10 (rosmantuzumab), PRI-724 and UC-961 (cirmtuzumab) are in clinical trials for cancer patients. Different classes of anti-WNT signaling therapeutics are necessary for the treatment of APC/CTNNB1-, RNF43/ZNRF3/RSPO2/RSPO3- and ROR1-types of human cancers. By contrast, Dickkopf-related protein 1 (DKK1), SOST and glycogen synthase kinase 3β (GSK3β) are targets of pro-WNT signaling therapy, and anti-DKK1 (BHQ880 and DKN-01) and anti-SOST (blosozumab, BPS804 and romosozumab) monoclonal antibodies are being tested in clinical trials for cancer patients and osteoporotic post-menopausal women. WNT-targeting therapeutics have also been applied as reagents for in vitro stem-cell processing in the field of regenerative medicine.

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“…After 48-h infection, cells were selected for 2 wk with puromycin at 1 μg/mL. Immortalization was confirmed by telomerase activity and length analysis as previously published (52,53). Population Doubling and Proliferation of Primary and Immortalized Cells.…”

Section: Methodsmentioning

confidence: 99%

Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts

Liu

Chang

Grinnell

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The most common genetic alterations for familial thoracic aortic aneurysms and dissections (TAAD) are missense mutations in vascular smooth muscle (SM) α-actin encoded by ACTA2. We focus here on ACTA2-R258C, a recurrent mutation associated with early onset of TAAD and occlusive moyamoya-like cerebrovascular disease. Recent biochemical results with SM α-actin-R258C predicted that this variant will compromise multiple actin-dependent functions in intact cells and tissues, but a model system to measure R258C-induced effects was lacking. We describe the development of an approach to interrogate functional consequences of actin mutations in affected patient-derived cells. Primary dermal fibroblasts from R258C patients exhibited increased proliferative capacity compared with controls, consistent with inhibition of growth suppression attributed to SM α-actin. Telomeraseimmortalized lines of control and R258C human dermal fibroblasts were established and SM α-actin expression induced with adenovirus encoding myocardin-related transcription factor A, a potent coactivator of ACTA2. Two-dimensional Western blotting confirmed induction of both wild-type and mutant SM α-actin in heterozygous ACTA2-R258C cells. Expression of mutant SM α-actin in heterozygous ACTA2-R258C fibroblasts abrogated the significant effects of SM α-actin induction on formation of stress fibers and focal adhesions, filamentous to soluble actin ratio, matrix contraction, and cell migration. These results demonstrate that R258C dominantly disrupts cytoskeletal functions attributed to SM α-actin in fibroblasts and are consistent with deficiencies in multiple cytoskeletal functions. Thus, cellular defects due to this ACTA2 mutation in both aortic smooth muscle cells and adventitial fibroblasts may contribute to development of TAAD and proliferative occlusive vascular disease.thoracic aortic aneurysms | ACTA2 mutation | vascular disease | cell migration | human fibroblasts

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Disruption of Wnt/β-Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human Cells

Cited by 62 publications

References 62 publications

The Wnt signaling pathway in cancer

The Wnt signaling pathway in cancer

Molecular genetics and targeted therapy of WNT-related human diseases (Review)

Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts

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