Inhibition of LEF1-Mediated DCLK1 by Niclosamide Attenuates Colorectal Cancer Stemness

Park, So Yeon; Kim, Ji Young; Choi, Jang Hyun; Kim, Jee Heun; Lee, Choong Jae; Singh, Pomila; Sarkar, Shubhashish; Baek, Jeong‐Heum; Nam, Jeong Seok

doi:10.1158/1078-0432.ccr-18-1232

Cited by 54 publications

(51 citation statements)

References 49 publications

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“…Thus, LEF1 is considered a potential therapeutic target for cancer treatment. LEF1 knock-down and suppression using shRNA and small molecules decreased cell growth in high LEF1 expressing cancer cells [17,18]. In this study, we found that LEF1 is highly expressed in A375, A2058, and G361 melanoma but not various lung cancer cells.…”

Section: Discussionmentioning

confidence: 52%

“…Thus, LEF1 is a promising molecular target for cancer treatment. Indeed, several studies have shown that LEF1 silencing attenuates cancer proliferation and induces apoptosis in glioblastoma multiforme (GBM) and colorectal cancer [17,18]. Furthermore, decreased cellular motility and invasiveness have been observed in LEF1 knocked-down colorectal cancer cells [19].…”

Section: Introductionmentioning

confidence: 99%

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Cinobufagin Suppresses Melanoma Cell Growth by Inhibiting LEF1

Kim

Fang

Lim

et al. 2020

IJMS

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Constitutive activation of the β-catenin dependent canonical Wnt signaling pathway, which enhances tumor growth and progression in multiple types of cancer, is commonly observed in melanoma. LEF1 activates β-catenin/TCF4 transcriptional activity, promoting tumor growth and progression. Although several reports have shown that LEF1 is highly expressed in melanoma, the functional role of LEF1 in melanoma growth is not fully understood. While A375, A2058, and G361 melanoma cells exhibit abnormally high LEF1 expression, lung cancer cells express lower LEF1 levels. A luciferase assay-based high throughput screening (HTS) with a natural compound library showed that cinobufagin suppressed β-catenin/TCF4 transcriptional activity by inhibiting LEF1 expression. Cinobufagin decreases LEF1 expression in a dose-dependent manner and Wnt/β-catenin target genes such as Axin-2, cyclin D1, and c-Myc in melanoma cell lines. Cinobufagin sensitively attenuates cell viability and induces apoptosis in LEF1 expressing melanoma cells compared to LEF1-low expressing lung cancer cells. In addition, ectopic LEF1 expression is sufficient to attenuate cinobufagin-induced apoptosis and cell growth retardation in melanoma cells. Thus, we suggest that cinobufagin is a potential anti-melanoma drug that suppresses tumor-promoting Wnt/β-catenin signaling via LEF1 inhibition.

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Section: Discussionmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

Cinobufagin Suppresses Melanoma Cell Growth by Inhibiting LEF1

Kim

Fang

Lim

et al. 2020

IJMS

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“…Niclosamide is an FDA-approved anthelmintic drug 124,125 that suppresses multiple CSC signalling pathways, such as the Wnt, Notch, STAT3 and NF-κB pathways. 126 In addition to targeting mitochondria to induce cell cycle arrest, growth suppression, and apoptosis in cancer cells, niclosamide inhibits CSCs, providing further evidence that it represents a promising agent for cancer therapy.…”

Section: Niclosamidementioning

confidence: 99%

“…127,128 Recently, niclosamide was shown to inhibit the CSC population and their self-renewal activity in colorectal cancer (CRC) cells, leading to irreversible destruction of tumour-initiating potential in vivo. 124 In a trial of cisplatin-induced oral CSC enrichment, application of niclosamide suppressed this process. Consequently, ALDH + OSCC cells are more sensitive to cisplatin therapy.…”

Section: Niclosamidementioning

confidence: 99%

<p>Self-Renewal Signalling Pathway Inhibitors: Perspectives on Therapeutic Approaches for Cancer Stem Cells</p>

Zhu¹,

Shen²,

Chen³

et al. 2020

OTT

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The poor survival and prognosis of individuals with cancer are often attributed to tumour relapse and metastasis, which may be due to the presence of cancer stem cells (CSCs). CSCs have the characteristics of self-renewal, differentiation potential, high carcinogenicity, and drug resistance. In addition, CSCs exhibit many characteristics similar to those of embryonic or tissue stem cells while displaying persistent abnormal activation of self-renewal pathways associated with development and tissue homeostasis, including the Wnt, Notch, Hedgehog (Hh), TGF-β, JAK/STAT3, and NF-κB pathways. Therefore, we can eliminate CSCs by targeting these self-renewal pathways to constrain stem cell replication, survival and differentiation. At the same time, we cannot neglect the ping-pong effect of the tumour microenvironment, which releases cytokines and promotes self-renewal pathways in CSCs. Recently, meaningful progress has been made in the study of inhibitors of self-renewal pathways in tumours. This review primarily summarizes several representative and novel agents targeting these self-renewal signalling pathways and the tumour microenvironment and that represent a promising strategy for treating refractory and recurrent cancer.

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“…In addition, Ji et al (2018) revealed that miR-15b by targeting DCLK1 not only repress self-renewal and tumorigenicity of CRC, but also improves sensitivity of cancer cells to chemo/radiotherapy [8]. Recently, it was shown that Niclosamide (an FDA-approved anthelmintic drug) prevents lymphoid enhancer-binding factor 1 (LEF1)-mediated transcription of DCLK1 and this led to attenuate cancer stemness and sensitizes CRC to chemoradiation [14]. Taken together, it seems that inhibition of DCLK1 restores the radiosensitivity of cancer cells and provides a novel target for the treatment of CRC.…”

mentioning

confidence: 99%