Phenethyl isothiocyanate inhibits colorectal cancer stem cells by suppressing Wnt/β‐catenin pathway

Chen, Yue; Li, Yuan; Wang, Xiaoqian; Meng, Yu; Zhang, Qi; Zhu, Jianyun; Chen, Jiaqi; Cao, Wanshuang; Wang, Xueqi; Xie, Chunfeng; Li, Xiaoting; Geng, Shanshan; Wu, Jieshu; Zhong, Caiyun; Han, Hongmei

doi:10.1002/ptr.6183

Cited by 48 publications

(38 citation statements)

References 35 publications

(36 reference statements)

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“…Several other natural products have been found to down-regulate the expression of β-catenin, including resveratrol ( Mitani et al., 2014 ; Mineda et al., 2019 ), phenethyl isothiocyanate (PEITC) ( Chen et al., 2018 ), gigantol ( Yu et al., 2018 ), polysaccharide from Phellinus linteus ( Song et al., 2011 ), and riccardin D ( Liu et al., 2012 ). Among them, resveratrol and PEITC are two well-documented dietary anticancer chemopreventive compounds with multiple molecular targets ( Mitani et al., 2014 ; Chen et al., 2018 ; Mineda et al., 2019 ). Recent studies have shown that resveratrol and PEITC also inhibit the β-catenin signaling; however, the importance of β-catenin in their anticancer activity is yet to be determined ( Mitani et al., 2014 ; Chen et al., 2018 ; Mineda et al., 2019 ).…”

Section: Natural Product Inhibitors Of β-Catenin Signaling Pathwaymentioning

confidence: 99%

Targeting β-Catenin Signaling by Natural Products for Cancer Prevention and Therapy

et al. 2020

Front. Pharmacol.

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The mutations and deregulation of Wnt signaling pathway occur commonly in human cancer and cause the aberrant activation of b-catenin and b-catenin-dependent transcription, thus contributing to cancer development and progression. Therefore, bcatenin has been demonstrated as a promising target for cancer prevention and therapy. Many natural products have been characterized as inhibitors of the b-catenin signaling through down-regulating b-catenin expression, modulating its phosphorylation, promoting its ubiquitination and proteasomal degradation, inhibiting its nuclear translocation, or other molecular mechanisms. These natural product inhibitors have shown preventive and therapeutic efficacy in various cancer models in vitro and in vivo. In the present review, we comprehensively discuss the natural product b-catenin inhibitors, their in vitro and in vivo anticancer activities, and underlying molecular mechanisms. We also discuss the current b-catenin-targeting strategies and other potential strategies that may be examined for identifying new b-catenin inhibitors as cancer preventive and therapeutic drugs.

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Section: Natural Product Inhibitors Of β-Catenin Signaling Pathwaymentioning

confidence: 99%

Targeting β-Catenin Signaling by Natural Products for Cancer Prevention and Therapy

et al. 2020

Front. Pharmacol.

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“…Immunoblotting analysis was performed as described previously 38 . In brief, 40 μg of total proteins in 15 μL were subject to 7.5-10% SDS-PAGE, transferred to nitrocellulose filter membrane (Millipore, Billerica, MA, USA), exposed to the antibodies, and detected by Chemiluminescence western blotting reagents (Cell Signaling Technology, Danvers, MA).…”

Section: Immunoblotting Analysismentioning

confidence: 99%

TAp63α targeting of Lgr5 mediates colorectal cancer stem cell properties and sulforaphane inhibition

et al. 2020

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Cancer stem cells (CSCs) have an established role in cancer progression and therapeutic resistance. The p63 proteins are important transcription factors which belong to the p53 family, but their function and mechanism in CSCs remain elusive. Here, we investigated the role of TAp63α in colorectal CSCs and the effects of sulforaphane on TAp63α. We found that TAp63α was upregulated in spheres with stem cell properties compared to the parental cells. Overexpression of TAp63α promoted self-renewal capacity and enhanced CSC markers expression in colorectal sphere-forming cells. Furthermore, we showed that TAp63α directly bound to the promoter region of Lgr5 to enhance its expression and activate its downstream β-catenin pathway. Functional experiments revealed that sulforaphane suppressed the stemness of colorectal CSCs both in vitro and in vivo. Upregulation of TAp63α attenuated the inhibitory effect of sulforaphane on colorectal CSCs, indicating the role of TAp63α in sulforaphane suppression of the stemness in colorectal cancer. The present study elucidated for the first time that TAp63α promoted CSCs through targeting Lgr5/β-catenin axis and participated in sulforaphane inhibition of the stem cell properties in colorectal cancer.

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“…In addition, the levels of β-catenin, a transcription factor that contributes to the expression of many CSC genes [31], were significantly reduced after incubation with PEITC (Figure 7a). reported that PEITC significantly inhibits sphere formation in colorectal cancer by targeting the Wnt/β-catenin pathway [54]. Importantly, incubation with PEITC promoted ROS production ( Figure 5b) and decreased GSH levels (Figure 5c).…”

Section: Discussionmentioning

confidence: 82%

“…Our results showed that PEITC could eliminate the CSC population in MDA-MB-231/IR cells, as evidenced by the significant inhibition of mammosphere formation, the CD44 + /CD24 − population, and ALDH activity (Figure 6a-c). PEITC has been reported to target CSC compartments in a variety of cancers, including cervical cancer [53], colon cancer [33], colorectal cancer [54], and HeLa cancer cells [10]. Recently, Koschorke et al (2019) found that PEITC can target HER-2 positive BCSCs, and this effect was enhanced in combination with trastuzumab therapy [55].…”

Section: Discussionmentioning

confidence: 99%

Phenethyl Isothiocyanate Suppresses Stemness in the Chemo- and Radio-Resistant Triple-Negative Breast Cancer Cell Line MDA-MB-231/IR Via Downregulation of Metadherin

Nguyen

Moon

Ediriweera

et al. 2020

Cancers

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Resistance to chemotherapy and radiation therapy is considered a major therapeutic barrier in breast cancer. Cancer stem cells (CSCs) play a prominent role in chemo and radiotherapy resistance. The established chemo and radio-resistant triple-negative breast cancer (TNBC) cell line MDA-MB-231/IR displays greater CSC characteristics than the parental MDA-MB-231 cells. Escalating evidence demonstrates that metadherin (MTDH) is associated with a number of cancer signaling pathways as well as breast cancer therapy resistance, making it an attractive therapeutic target. Kaplan–Meier plot analysis revealed a correlation between higher levels of MTDH and shorter lifetimes in breast cancer and TNBC patients. Moreover, there was a positive correlation between the MTDH and CD44 expression levels in The Cancer Genome Atlas breast cancer database. We demonstrate that MTDH plays a pivotal role in the regulation of stemness in MDA-MB-231/IR cells. Knockdown of MTDH in MDA-MB-231/IR cells resulted in a reduction in the CSC population, aldehyde dehydrogenase activity, and major CSC markers, including β-catenin, CD44+, and Slug. In addition, MTDH knockdown increased reactive oxygen species (ROS) levels in MDA-MB-231/IR cells. We found that phenethyl isothiocyanate (PEITC), a well-known pro-oxidant phytochemical, suppressed stemness in MDA-MB-231/IR cells through ROS modulation via the downregulation of MTDH. Co-treatment of PEITC and N-Acetylcysteine (a ROS scavenger) caused alterations in PEITC induced cell death and CSC markers. Moreover, PEITC regulated MTDH expression at the post-transcriptional level, which was confirmed using cycloheximide, a protein synthesis inhibitor.

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Phenethyl isothiocyanate inhibits colorectal cancer stem cells by suppressing Wnt/β‐catenin pathway

Cited by 48 publications

References 35 publications

Targeting β-Catenin Signaling by Natural Products for Cancer Prevention and Therapy

Targeting β-Catenin Signaling by Natural Products for Cancer Prevention and Therapy

TAp63α targeting of Lgr5 mediates colorectal cancer stem cell properties and sulforaphane inhibition

Phenethyl Isothiocyanate Suppresses Stemness in the Chemo- and Radio-Resistant Triple-Negative Breast Cancer Cell Line MDA-MB-231/IR Via Downregulation of Metadherin

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