Selective Wnt/β-catenin Small-molecule Inhibitor CWP232228 Impairs Tumor Growth of Colon Cancer

Kim, Jin Young; Park, Geumi; Krishnan, Manigandan; Ha, Eunyoung; Chun, Kyung‐Soo

doi:10.21873/anticanres.13514

Cited by 14 publications

(14 citation statements)

References 24 publications

(24 reference statements)

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“…Consequently, aberrant activation of the Wnt signalling pathway might play different roles in the development and progression of MSS- and MSI-H-CRC. These findings are especially important in the context of evolving new target therapies of β-catenin which as yet, however, have not been incorporated into clinical practice [ 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

The majority of β-catenin mutations in colorectal cancer is homozygous

et al. 2020

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Background β-catenin activation plays a crucial role for tumourigenesis in the large intestine but except for Lynch syndrome (LS) associated cancers stabilizing mutations of β-catenin gene (CTNNB1) are rare in colorectal cancer (CRC). Previous animal studies provide an explanation for this observation. They showed that CTNNB1 mutations induced transformation in the colon only when CTNNB1 was homozygously mutated or when membranous β-catenin binding was hampered by E-cadherin haploinsufficiency. We were interested, if these mechanisms are also found in human CTNNB1 mutated CRCs. Results Among 869 CRCs stabilizing CTNNB1 mutations were found in 27 cases. Homo- or hemizygous CTNNB1 mutations were detected in 74% of CTNNB1 mutated CRCs (13 microsatellite instabile (MSI-H), 7 microsatellite stabile (MSS)) but only in 3% (1/33) of extracolonic CTNNB1 mutated cancers. In contrast to MSS CRC, CTNNB1 mutations at codon 41 or 45 were highly selected in MSI-H CRC. Of the examined three CRC cell lines, β-catenin and E-cadherin expression was similar in cell lines without or with hetereozygous CTNNB1 mutations (DLD1 and HCT116), while a reduced E-cadherin expression combined with cytoplasmic accumulation of β-catenin was found in a cell line with homozygous CTNNB1 mutation (LS180). Reduced expression of E-cadherin in human MSI-H CRC tissue was identified in 60% of investigated cancers, but no association with the CTNNB1 mutational status was found. Conclusions In conclusion, this study shows that in contrast to extracolonic cancers stabilizing CTNNB1 mutations in CRC are commonly homo- or hemizygous indicating a higher threshold of β-catenin stabilization to be required for transformation in the colon as compared to extracolonic sites. Moreover, we found different mutational hotspots in CTNNB1 for MSI-H and MSS CRCs suggesting a selection of different effects on β-catenin stabilization according to the molecular pathway of tumourigenesis. Reduced E-cadherin expression in CRC may further contribute to higher levels of transcriptionally active β-catenin, but it is not directly linked to the CTNNB1 mutational status.

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Section: Discussionmentioning

confidence: 99%

The majority of β-catenin mutations in colorectal cancer is homozygous

et al. 2020

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“…Previous studies have revealed that aberration of the Wnt/β-catenin signaling pathway significantly contributes to the malignant transformation of colon cancer (19,20). inhibition of Wnt/β-catenin is suggested to be an anti-tumor mechanism in colon cancer (21). in the absence of Wnt, the phosphoprotein scaffold dishevelled3 (dsh3) promotes the destabilization of β-catenin 1 mrna (22).…”

Section: Overexpression Of G3bp1 Facilitates the Progression Of Colonmentioning

confidence: 99%

“…The β-catenin protein is controlled by a protein complex that consists of axis inhibitor (Axin), adenomatous polyposis coil (APC), casein kinase 1α and glycogen synthase kinase 3β, and is confined in the cytoplasm ( 22 ). However, β-catenin is increased in cytoplasm and eventually translocates into the nucleus once Wnt signaling is activated, inducing the transcription of target genes, including c-myc, a cell proliferation-associated gene ( 21 ). G3BP1 has been identified to be a Dsh-associated protein that is methylated in response to Wnt3a and negatively regulates β-catenin expression ( 23 ).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of G3BP1 facilitates the progression of colon cancer by activating β‑catenin signaling

Wang

Zhong

et al. 2020

Mol Med Rep

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ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) has been reported to be of importance in the occurrence and development of colon cancer. However, the underlying mechanisms remain largely unknown. Therefore, the aim of the present study was to investigate the role of Wnt/β-catenin signaling in G3BP1-mediated colon cancer progression. The expression of G3BP1 in colon tissues and cells was detected via reverse transcription-quantitative Pcr, western blotting and immunohistochemistry. Gain-of-function assays were performed in colon cancer rKo cells, which have a relatively low expression of G3BP1, while loss-of-function assays were performed in SW620 colon cancer cells, which have a relatively high expression of G3BP1. cell proliferation, apoptosis and tumorigenesis were assessed using cell counting Kit-8, flow cytometry and tumor-bearing mice assays, respectively. The results demonstrated that G3BP1 expression was significantly upregulated in colon cancer tissues and cells compared with healthy colon tissues and cells. it was found that high expression of G3BP1 was closely associated with the poor prognosis and advanced clinical process in patients with colon cancer. overexpression of G3BP1 in rKo cells enhanced their proliferative ability and decreased their apoptosis tendency, while knockdown of G3BP1 inhibited SW620 cell proliferation and induced apoptosis. in addition, G3BP1 interacted with β-catenin and upregulated its expression and nuclear accumulation. It was identified that β-catenin knockdown abolished the effects of G3BP1 on the enhancement of cell proliferation in vitro and tumor formation in vivo, as well as the inhibition of cell apoptosis. in conclusion, the present study demonstrated that G3BP1 promoted the progression of colon cancer by activating β-catenin signaling, which provided novel evidence for the role of G3BP1 in colon cancer.

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“…CWP232228 prevents binding of β-catenin to TCF proteins in the nucleus thereby reducing tumor formation and metastasis. In vivo CWP232228 suppressed tumor growth in colon cancer models [60]. CWP232291, closely related to CWP232228, completed a phase I trial.…”

Section: Metastasis Outgrowth-intervention Of Settlementmentioning

confidence: 99%

Small Ones to Fight a Big Problem—Intervention of Cancer Metastasis by Small Molecules

Kobelt

Dahlmann

Dumbani

et al. 2020

Cancers

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Metastasis represents the most lethal attribute of cancer and critically limits successful therapies in many tumor entities. The clinical need is defined by the fact that all cancer patients, who have or who will develop distant metastasis, will experience shorter survival. Thus, the ultimate goal in cancer therapy is the restriction of solid cancer metastasis by novel molecularly targeted small molecule based therapies. Biomarkers identifying cancer patients at high risk for metastasis and simultaneously acting as key drivers for metastasis are extremely desired. Clinical interventions targeting these key molecules will result in high efficiency in metastasis intervention. In result of this, personalized tailored interventions for restriction and prevention of cancer progression and metastasis will improve patient survival. This review defines crucial biological steps of the metastatic cascade, such as cell dissemination, migration and invasion as well as the action of metastasis suppressors. Targeting these biological steps with tailored therapeutic strategies of intervention or even prevention of metastasis using a wide range of small molecules will be discussed.

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Selective Wnt/β-catenin Small-molecule Inhibitor CWP232228 Impairs Tumor Growth of Colon Cancer

Cited by 14 publications

References 24 publications

The majority of β-catenin mutations in colorectal cancer is homozygous

The majority of β-catenin mutations in colorectal cancer is homozygous

Overexpression of G3BP1 facilitates the progression of colon cancer by activating β‑catenin signaling

Small Ones to Fight a Big Problem—Intervention of Cancer Metastasis by Small Molecules

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