Tryptophan derivatives regulate the transcription of Oct4 in stem-like cancer cells

Cheng, Jie; Li, Wenxin; Kang, Bo; Zhou, Yi; Song, Jingkuan; Dan, Songsong; Yang, Ying; Zhang, Xiaoqian; Li, Jingchao; Yin, Shengyong; H, Cao; Yao, Hang; Zhu, Chenggang; Yi, Wen; Zhao, Qiu; Xu, Xiaowei; Zheng, Min; Zheng, Shusen; Li, Lanjuan; Shen, Binghui; Wang, Yingjie

doi:10.1038/ncomms8209

Cited by 96 publications

(99 citation statements)

References 35 publications

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“…TDO2 catalyzes tryptophan into kynurenine in the kynurenine pathway [15,16]. It is well known that tryptophan derivatives such as 6-formylindolo[3, 2-b]carbazole, kynurenine, and 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) are natural ligands of the AhR [39]. The synthetic agonist of the AhR can downregulate the master pluripotency factor Oct4 in stem-like breast cancer cell lines and inhibit their proliferation and metastasis [39], indicating that synthetic ITE can induce the differentiation of stem-like cancer cells and reduces their tumorigenic potential.…”

Section: Discussionmentioning

confidence: 99%

“…It is well known that tryptophan derivatives such as 6-formylindolo[3, 2-b]carbazole, kynurenine, and 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) are natural ligands of the AhR [39]. The synthetic agonist of the AhR can downregulate the master pluripotency factor Oct4 in stem-like breast cancer cell lines and inhibit their proliferation and metastasis [39], indicating that synthetic ITE can induce the differentiation of stem-like cancer cells and reduces their tumorigenic potential. In fact, it has been reported that reduction of endogenous ITE levels in cancer cells by tryptophan deprivation leads to elevation of Oct4, which is the master pluripotency factor [39].…”

Section: Discussionmentioning

confidence: 99%

“…The synthetic agonist of the AhR can downregulate the master pluripotency factor Oct4 in stem-like breast cancer cell lines and inhibit their proliferation and metastasis [39], indicating that synthetic ITE can induce the differentiation of stem-like cancer cells and reduces their tumorigenic potential. In fact, it has been reported that reduction of endogenous ITE levels in cancer cells by tryptophan deprivation leads to elevation of Oct4, which is the master pluripotency factor [39]. Therefore, overexpression of TDO2 could reduce the tryptophan level in cancer cells and induce Oct4 expression.…”

Section: Discussionmentioning

confidence: 99%

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TDO2 Overexpression Is Associated with Cancer Stem Cells and Poor Prognosis in Esophageal Squamous Cell Carcinoma

et al. 2018

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Objective: Esophageal cancer is one of the deadliest cancers in the world, and the main subtype is esophageal squamous cell carcinoma (ESCC), which comprises 90% of cases. Expression of tryptophan 2,3-dioxygenase (TDO2), an enzyme involved in tryptophan catabolism, has been linked with tumor survival and poor prognosis of brain and breast cancer. However, no studies have investigated the potential role of TDO2 in esophageal cancer. Here we explored the expression and biological significance of TDO2 in ESCC. Methods: TDO2 protein expression was evaluated in 90 ESCC tissue samples by immunohistochemistry. TDO2 function in ESCC cell lines and spheroid colony formation were evaluated by RNA interference (RNAi). Results: TDO2 overexpression was associated with tumor stage, recurrence status, and the CD44 cancer stem cell marker in ESCC. TDO2 overexpression was correlated with poor outcome of ESCC patients. Inhibition of TDO2 expression by RNAi in TE-10 and TE-11 cell lines reduced both the number and the size of spheroid colonies as well as cell proliferation. Knockdown of TDO2 expression also induced inactivation of the epidermal growth factor receptor signaling pathway. Conclusion: Our results imply that TDO2 could play an important role in the progression of ESCC. Furthermore, TDO2 may be a potential therapeutic target in ESCC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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TDO2 Overexpression Is Associated with Cancer Stem Cells and Poor Prognosis in Esophageal Squamous Cell Carcinoma

et al. 2018

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“…ITE was first identified in porcine lung tissues [14]. Recently, ITE was found to be present in human tumor cells in vitro [15]. Thus far, the physiological level of ITE has not been reported in any tissue in any species.…”

Section: Introductionmentioning

confidence: 99%

“…However, ITE can regulates a variety of cellular functions. For instance, ITE can induce the differentiation of stem-like cancer cells and reduce their tumorigenic potential [15]. ITE also suppresses immunologic responses by directly targeting dendritic and T cells [16,17].…”

Section: Introductionmentioning

confidence: 99%

ITE Suppresses Angiogenic Responses in Human Artery and Vein Endothelial Cells: Differential Roles of AhR

Wang

Zou

et al. 2017

Reproductive Toxicology

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Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor is involved in regulation of many essential biological processes including vascular development and angiogenesis. 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is an AhR ligand, which regulates immune responses and cancer cell growth. However, the roles of the ITE/AhR pathway in mediating placental angiogenesis remains elusive. Here, we determined if ITE affected placental angiogenic responses via AhR in human umbilical vein (HUVECs) and artery endothelial (HUAECs) cells in vitro. We observed that ITE dose- and time-dependently inhibited proliferation and viability of HUAECs and HUVECs, whereas it inhibited migration of HUAECs, but not HUVECs. While AhR siRNA significantly suppressed AhR protein expression in HUVECs and HUAECs, it attenuated the ITE-inhibited angiogenic responses of HUAECs, but not HUVECs. Collectively, ITE suppressed angiogenic responses of HUAECs and HUVECs, dependent and independent of AhR, respectively. These data suggest that ITE may regulate placental angiogenesis.

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Binding Mode and Structure–Activity Relationships of ITE as an Aryl Hydrocarbon Receptor (AhR) Agonist

et al. 2018

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Discovered as a modulator of the toxic response to environmental pollutants, aryl hydrocarbon receptor (AhR) has recently gained attention for its involvement in various physiological and pathological pathways. AhR is a ligand-dependent transcription factor activated by a large array of chemical compounds, which include metabolites of l-tryptophan (l-Trp) catabolism as endogenous ligands of the receptor. Among these, 2-(1'H-indole-3'-carbonyl)thiazole-4-carboxylic acid methyl ester (ITE) has attracted interest in the scientific community, being endowed with nontoxic, immunomodulatory, and anticancer AhR-mediated functions. So far, no information about the binding mode and interactions of ITE with AhR is available. In this study, we used docking and molecular dynamics to propose a putative binding mode of ITE into the ligand binding pocket of AhR. Mutagenesis studies were then instrumental in validating the proposed binding mode, identifying His 285 and Tyr 316 as important key residues for ligand-dependent receptor activation. Finally, a set of ITE analogues was synthesized and tested to further probe molecular interactions of ITE to AhR and characterize the relevance of specific functional groups in the chemical structure for receptor activity.

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Tryptophan derivatives regulate the transcription of Oct4 in stem-like cancer cells

Cited by 96 publications

References 35 publications

TDO2 Overexpression Is Associated with Cancer Stem Cells and Poor Prognosis in Esophageal Squamous Cell Carcinoma

TDO2 Overexpression Is Associated with Cancer Stem Cells and Poor Prognosis in Esophageal Squamous Cell Carcinoma

ITE Suppresses Angiogenic Responses in Human Artery and Vein Endothelial Cells: Differential Roles of AhR

Binding Mode and Structure–Activity Relationships of ITE as an Aryl Hydrocarbon Receptor (AhR) Agonist

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