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 γ-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.
Highlights
Cervical cancer is the fourth most common cancer in women, accounting for 6.6% of all cancers in women and with an estimated 570,000 new cases and 311,000 deaths in 2018 [1]
To explore the potential function of IDO1 in cancer stem cells (CSCs) behavior, we firstly examined its expression between two cultivation methods of conventional two-dimensional (2D)
In addition to protein level, the IDO1 activity, which was determined by the conversion of kynurenine from tryptophan using Ehlrich reagent, was increased in HeLa and SiHa tumorspheres in comparison to 2D cultured cells (Figure 1C)
Summary
Cervical cancer is the fourth most common cancer in women, accounting for 6.6% of all cancers in women and with an estimated 570,000 new cases and 311,000 deaths in 2018 [1]. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme responsible for the oxidative metabolism of tryptophan, which converts tryptophan to kynurenine and inhibits the activation and proliferation of T cells [11]. It has been reported that cervical cancer cells with IDO1 expression were mostly found in cells at the invasive front [13] and the high ratio of kynurenine/tryptophan was positively correlated with lymph node metastasis, tumor size and low disease-free survival of cervical cancer patients [14], suggesting that IDO1 may be involved in the progression of cervical cancers. In addition to the T cell suppression activity, IDO1 has been reported to support cancer growth in a non-immunomodulation way. The non-immune functions of IDO1 have been reported in some cancer types, the involvement of IDO1 in the characteristics of cervical CSCs remains unclear
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