Reciprocal Regulation Between Indoleamine 2,3-Dioxigenase 1 and Notch1 Involved in Radiation Response of Cervical Cancer Stem Cells

doi:10.3390/cancers12061547

中山醫學大學機構典藏 CSMUIR > 中山醫學大學研究成果 > 期刊論文 > Item 310902500/24279

Please use this identifier to cite or link to this item: https://ir.csmu.edu.tw:8080/ir/handle/310902500/24279

Title:	Reciprocal Regulation Between Indoleamine 2,3-Dioxigenase 1 and Notch1 Involved in Radiation Response of Cervical Cancer Stem Cells
Authors:	Low, HY;Lee, YC;Lee, YJ;Wang, HL;Chen, YI;Chien, PJ;Li, ST;Chang, WW
Keywords:	IDO1;notch1;radiation;cervical cancer;cancer stem cells
Date:	2020
Issue Date:	2022-08-09T07:59:41Z (UTC)
Publisher:	MDPI
Abstract:	Cervical cancer is the fourth most common cancer in women around the world. Cancer stem cells (CSCs) are responsible for cancer initiation, as well as resistance to radiation therapy, and are considered as the effective target of cancer therapy. Indoleamine 2,3-dioxygenase 1 (IDO1) mediates tryptophan metabolism and T cell suppression, but the immune-independent function of IDO1 in cancer behavior is not fully understood. Using tumorsphere cultivation for enriched CSCs, we firstly found that IDO1 was increased in HeLa and SiHa cervical cancer cells and in these two cell lines after radiation treatment. The radiosensitivity of HeLa and SiHa tumorsphere cells was increased after the inhibition of IDO1 through RNA interference or by the treatment of INCB-024360, an IDO1 inhibitor. With the treatment of kynurenine, the first breakdown product of the IDO1-mediated tryptophan metabolism, the radiosensitivity of HeLa and SiHa cells decreased. The inhibition of Notch1 by shRNA downregulated IDO1 expression in cervical CSCs and the binding of the intracellular domain of Notch (NICD) on the IDO1 promoter was reduced by Ro-4929097, a gamma-secretase inhibitor. Moreover, the knockdown of IDO1 also decreased NICD expression in cervical CSCs, which was correlated with the reduced binding of aryl hydrocarbon receptor nuclear translocator to Notch1 promoter. In vivo treatment of INCB-0234360 sensitized SiHa xenograft tumors to radiation treatment in nude mice through increased DNA damage. Furthermore, kynurenine increased the tumorsphere formation capability and the expression of cancer stemness genes including Oct4 and Sox2. Our data provide a reciprocal regulation mechanism between IDO1 and Notch1 expression in cervical cancer cells and suggest that the IDO1 inhibitors may potentially be used as radiosensitizers.
URI:	http://dx.doi.org/10.3390/cancers12061547 https://www.webofscience.com/wos/woscc/full-record/WOS:000549269500001 https://ir.csmu.edu.tw:8080/handle/310902500/24279
Relation:	CANCERS ,2020 ,v12 ,issue 6
Appears in Collections:	[中山醫學大學研究成果] 期刊論文

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