AR - GR开关调节不同的TDO2-Kyn-AhR信号传导,促进前列腺癌治疗诱导的休眠细胞的存活和复发。

IF 12.5 1区 生物学 Q1 CELL BIOLOGY
Sangsang Li, Yifan Zhang, Maoxing Luo, Weiwei Zhou, Yitong Chen, Dinglan Wu, Qiang Wei, Yan Chang, Hailiang Hu
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引用次数: 0

摘要

通过特定的癌症治疗,癌细胞可以被诱导到最初的休眠状态,但在随后的复发中,癌细胞可以作为治疗抵抗性的癌细胞被重新激活。尽管治疗诱导的休眠-再激活开关是肿瘤扩散和复发的重要过程,但对其潜在的分子机制,特别是代谢基础知之甚少。在这项研究中,我们证明了色氨酸分解代谢相关的色氨酸2,3-双加氧酶(TDO2) -犬尿氨酸(Kyn) -芳烃受体(AhR)信号轴既负责维持雄激素剥夺治疗(ADT)诱导的休眠前列腺癌细胞的存活,又促进休眠细胞的再激活及其复发生长,从而通过允许休眠-再激活开关促进治疗抗性的发展。在机制上,我们发现ADT上调TDO2的表达,产生Kyn,激活AhR,维持ADT诱导的休眠细胞的存活。有趣的是,从雄激素受体(AR)到糖皮质激素受体(GR)的转录因子转换调节了TDO2的持续表达,并通过相同的TDO2- kyn - ahr信号轴促进休眠细胞的再激活。此外,ADT后的肿瘤复发可以通过TDO2抑制剂或AhR抑制剂抑制TDO2- kyn -AhR信号传导而延迟。综上所述,我们描述了一个由色氨酸代谢介导的信号通路,调节肿瘤细胞的休眠和复发,并提出TDO2作为雄激素敏感前列腺癌患者联合ADT治疗的新靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
AR to GR switch modulates differential TDO2-Kyn-AhR signalling to promote the survival and recurrence of treatment-induced dormant cells in prostate cancer.

Cancer cells can be induced to dormancy initially by specific cancer therapies, but can be reactivated for subsequent relapse as therapy-resistant cancer cells. Although the treatment-induced dormancy-to-reactivation switch is an important process in tumour spread and recurrence, little is known about the underlying molecular mechanisms, particularly the metabolic underpinnings. In this study, we demonstrated that the tryptophan catabolism-related tryptophan 2,3-dioxygenase (TDO2) -kynurenine (Kyn) -aryl hydrocarbon receptor (AhR) signalling axis was responsible for both sustaining the survival of dormant prostate cancer cells induced by androgen deprivation therapy (ADT) and promoting the reactivation of dormant cells and their recurrent outgrowth, which facilitated the development of therapeutic resistance by allowing the dormancy-to-reactivation switch. Mechanistically, we found that ADT upregulated the expression of TDO2 to produce Kyn, which activated AhR and maintained the survival of ADT-induced dormant cells. Interestingly, the switch of transcription factors from the androgen receptor (AR) to the glucocorticoid receptor (GR) modulated the persistent expression of TDO2 and promoted the reactivation of dormant cells through the same TDO2-Kyn-AhR signalling axis. Additionally, tumour recurrence following ADT was delayed by pharmacological suppression of TDO2-Kyn-AhR signalling with a TDO2 inhibitor or an AhR inhibitor. In summary, we describe a signalling circuit mediated by tryptophan metabolism for regulating tumour cell dormancy and recurrence and propose TDO2 as a new target for the treatment of androgen-sensitive prostate cancer patients in combination with ADT.

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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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