Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Department of Oncology, Shanghai Putuo People's Hospital, School of Medicine, Tongji University, Shanghai, China.
Biochem Pharmacol. 2024 May;223:116172. doi: 10.1016/j.bcp.2024.116172. Epub 2024 Mar 27.
The enzyme tryptophan 2,3-dioxygenase (TDO2) has been implicated in the dysregulation across a variety of human cancers. Despite this association, the implications of TDO2 in the progression of bladder cancer have eluded thorough understanding. In this study, we demonstrate that TDO2 expression is notably elevated in bladder cancer tissues and serves as an unfavorable prognostic factor for overall survival. Through a series of biological functional assays, we have determined that TDO2 essentially enhances cell proliferation, metastatic potential, and imparts a decreased sensitivity to the chemotherapeutic agent cisplatin. Our mechanistic investigations reveal that TDO2 augments aryl hydrocarbon receptor (AhR) signaling pathways and subsequently upregulates the expression of SPARC and FILIP1L. Importantly, we have identified a positive correlation between TDO2 levels and the basal/squamous subtype of bladder cancer, and we provide evidence to suggest that TDO2 expression is modulated by the tumor suppressors RB1 and TP53. From a therapeutic perspective, we demonstrate that the targeted inhibition of TDO2 with the molecular inhibitor 680C91 markedly attenuates tumor growth and metastasis while concurrently enhancing the efficacy of cisplatin. These findings open a new therapeutic avenue for the management of bladder cancer.
色氨酸 2,3-双加氧酶（TDO2）已被牵涉到多种人类癌症的失调中。尽管存在这种关联，但 TDO2 在膀胱癌进展中的意义仍未得到充分理解。在这项研究中，我们证明 TDO2 表达在膀胱癌组织中显著升高，并作为总生存期的不利预后因素。通过一系列生物学功能测定，我们确定 TDO2 本质上增强了细胞增殖、转移潜能，并降低了对化疗药物顺铂的敏感性。我们的机制研究表明，TDO2 增强了芳香烃受体（AhR）信号通路，随后上调了 SPARC 和 FILIP1L 的表达。重要的是，我们发现 TDO2 水平与膀胱癌的基底/鳞状亚型之间存在正相关关系，并且我们提供的证据表明 TDO2 表达受肿瘤抑制因子 RB1 和 TP53 的调节。从治疗角度来看，我们证明了用分子抑制剂 680C91 靶向抑制 TDO2 可显著抑制肿瘤生长和转移，同时增强顺铂的疗效。这些发现为膀胱癌的治疗开辟了新的治疗途径。
