Novel mechanism linking noncanonical Wnt ligand induction to suppression of colorectal cancer cell proliferation.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 648-648
Author(s):  
Donald Peter Braun ◽  
Bani M Fagla ◽  
Irshad Ali
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Wnt Pathway ◽  
Fold Increase ◽  
Canonical Pathway ◽  
Unexpected Finding ◽  
Cancer Cell Proliferation ◽  
Pathway Gene ◽  
Proliferation And Differentiation

648 Background: Malignant tissues are characterized by uncontrolled proliferation and dysfunctional differentiation. A central pathway in the control of proliferation and differentiation is the Wnt pathway. Wnt function is mediated by a canonical pathway (CP) which utilizes β-catenin and stimulates cell proliferation, and a non-canonical pathway (NCP) independent of β-catenin involved with differentiation. Studies suggest that dysfunctional Wnt signaling results from imbalance of CP components. The possibility that modulation of NCP components are involved in this process has not been studied comprehensively. Given their importance in constraining CP signaling and proliferation, the purpose of this study was to determine the capacity of NCP components to suppress human colorectal cancer (CRC) proliferation. Methods: Short term, primary CRC lines were established from resected tumors from patients with metastatic and/or recurrent disease. CRC were treated with LiCl, an activator of the CP, Dkk1, an inhibitor of the CP, and IWP-2, a pan inhibitor of CP and NCP Wnt ligand secretion. CRC proliferation and Wnt pathway gene expression were determined by MTS assays and quantitative gene expression respectively. Results: Unexpectedly, CRC proliferation was inhibited significantly (p<0.01) by LiCl and stimulated modestly (ns) by Dkk1. This was associated with a 20 fold increase in gene expression for the NCP ligand, Wnt9A. LiCl treated cells incubated with IWP-2 reversed the unexpected LiCl-mediated suppression of CRC proliferation. Conclusions: The unexpected finding that LiCl suppresses proliferation and Dkk1 has the opposite effect indicate dysregulation of the Wnt pathway in CRC. Further support for this hypothesis is the fact that Wnt 9A, an NCP ligand is increased by LiCl in CRC, an effect that is not expected in non-malignant cells. That IWP-2, a pan Wnt ligand secretion inhibitor reverses these effects is consistent with these observations. This study is the first to demonstrate a correlation between NCP ligand induction and suppression of CRC proliferation and suggests that control of CRC proliferation may be achieved in patients by modalities that activate the NCP Wnt pathway.

Effects of SM08502, a novel, oral small-molecule inhibitor of Wnt pathway signaling, on gene expression and antitumor activity in colorectal cancer (CRC) models.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15185-e15185 ◽  
Author(s):  
Carine Bossard ◽  
Kevin Chiu ◽  
Heekyung Chung ◽  
John Duc Nguyen ◽  
Emily Creger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Antitumor Activity ◽  
Wnt Signaling ◽  
Cell Lines ◽  
Wnt Pathway ◽  
Pathway Gene ◽  
Hct 116

e15185 Background: Aberrant activation of Wnt signaling contributing to tumorigenesis is most commonly associated with CRC (90% harbor Wnt pathway mutations). SM08502, a novel, oral Wnt signaling pathway inhibitor, was evaluated in preclinical CRC models. Methods: In vitro Wnt signaling: assessed using TOPflash β-catenin/TCF reporter assay in SW480 human CRC cells. In vitro Wnt pathway gene expression: measured by qRT-PCR in SW480 and Wnt3a-stimulated cells (HEK-293T, IEC-6), and with the Nanostring Wnt pathway array (180 genes) across a panel of 16 CRC cell lines. In vitro cell proliferation: 17 CRC cell lines were used to test cell viability following treatment. In vivo antitumor activity: Oral SM08502 was tested in CRC mouse xenografts (SW480, HCT 116) and a PDX model over 20-21 days (QD, QOD). 24-hr pharmacodynamic (PD) analysis of Wnt pathway gene expression was done in SW480 tumor explants from mice following one 25 mg/kg dose. Results: SM08502 inhibited Wnt pathway signaling (EC50 = 46 nM) in SW480 cells. Wnt pathway gene expression was inhibited by SM08502 (0.3-3 µM) in Wnt3a-stimulated cells ( AXIN2, LEF1) and SW480 ( AXIN2, CTNNB1, LEF1, MYC, TCF7, TCF7L2) at 24 hrs ( P < .05 vs. vehicle) . Corresponding effects on protein expression were confirmed for all genes except CTNNB1, suggesting SM08502 acted independently of β-catenin. Nanostring array screening identified inhibition of LRP5, DVL2, BTRC, and ERBB2 by SM08502. Cell proliferation was inhibited in all 17 lines (avg. EC50 = 177 nM). In vivo, SM08502 was well tolerated and induced dose-dependent antitumor effects in xenografts and PDX models. Tumor growth inhibition for 25 mg/kg QD (max dose) was 83%, 56%, and 70% in SW480, HCT 116, and PDX, respectively. PD analysis showed significant inhibition ( P< .05 vs. vehicle) of TCF7, MYC, LRP5, DVL2, and BTRC expression 8 hrs post treatment. Conclusions: In preclinical CRC models, SM08502 was a potent inhibitor of Wnt pathway signaling and gene expression. It showed strong antitumor activity in human tumor models with activating Wnt pathway mutations. The safety, tolerability, and PK of SM08502 are being evaluated in an ongoing phase 1 study (NCT03355066).

scholarly journals Regulation of UHRF 1 by micro RNA ‐9 modulates colorectal cancer cell proliferation and apoptosis

2015 ◽  
Vol 106 (7) ◽  
pp. 833-839 ◽  
Author(s):  
Mingchen Zhu ◽  
Yijun Xu ◽  
Mengyuan Ge ◽  
Zhen Gui ◽  
Feng Yan
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Cancer Cell ◽  
Micro Rna ◽  
Colorectal Cancer Cell ◽  
Cancer Cell Proliferation ◽  
Proliferation And Apoptosis

HDAC3 overexpression and colon cancer cell proliferation and differentiation

2007 ◽  
Vol 47 (2) ◽  
pp. 137-147 ◽  
Author(s):  
Colleen C. Spurling ◽  
Cassandra A. Godman ◽  
Emily J. Noonan ◽  
Theodore P. Rasmussen ◽  
Daniel W. Rosenberg ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cell Proliferation ◽  
Cancer Cell ◽  
Colon Cancer Cell ◽  
Cancer Cell Proliferation ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation

scholarly journals Effects of low-to-moderate ethanol consumption on colonic growth and gene expression in young adult and middle-aged male rats

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243499
Author(s):  
Nicole Wells ◽  
Jacqueline Quigley ◽  
Jeremy Pascua ◽  
Natalie Pinkowski ◽  
Lama Almaiman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Cell Differentiation ◽  
Young Adult ◽  
Cell Growth ◽  
Alcohol Consumption ◽  
Ethanol Consumption ◽  
Ethanol Treatment ◽  
Middle Aged

Excessive alcohol consumption is a risk factor associated with colorectal cancer; however, some epidemiological studies have reported that moderate alcohol consumption may not contribute additional risk or may provide a protective effect reducing colorectal cancer risk. Prior research highlights the importance of proliferation, differentiation, and apoptosis as parameters to consider when evaluating colonic cell growth and tumorigenesis. The present study investigated whether chronic low-to-moderate ethanol consumption altered these parameters of colonic cell growth and expression of related genes. Twenty-four nondeprived young adult (109 days old) and 24 nondeprived middle-aged (420 days old) Wistar rats were randomly assigned to an ethanol-exposed or a water control group (n = 12/group). The ethanol group was provided voluntary access to a 20% v/v ethanol solution on alternate days for 13 weeks. Colon tissues were collected for quantitative immunohistochemical analyses of cell proliferation, differentiation and apoptosis using Ki-67, goblet cell and TUNEL, respectively. Gene expression of cyclin D1 (Ccnd1), Cdk2, Cdk4, p21waf1/cip1 (Cdkn1a), E-cadherin (Cdh1) and p53 were determined by quantitative real-time polymerase chain reaction in colonic scraped mucosa. Ethanol treatment resulted in a lower cell proliferation index and proliferative zone, and lower Cdk2 expression in both age groups, as well as trends toward lower Ccnd1 and higher Cdkn1a expression. Cell differentiation was modestly but significantly reduced by ethanol treatment only in older animals. Overall, older rats showed decreases in apoptosis and gene expression of Cdk4, Cdh1, and p53 compared to younger rats, but there was no observed effect of ethanol exposure on these measures. These findings suggest that low-to-moderate ethanol consumption improves at least one notable parameter in colonic tumorigenesis (cell proliferation) and associated gene expression regardless of age, however, selectively decreased cell differentiation among older subjects.

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