Zhou Yuan, Tang Jinlong, Weng Menghan, Zhang Honghe, Lai Maode
Department of Pathology and Run Run Shaw Hospital, Research Unit of Intelligence Classifification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
Department of Pathology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
Adv Sci (Weinh). 2025 Feb;12(6):e2413953. doi: 10.1002/advs.202413953. Epub 2024 Dec 16.
The functional and pharmacological significance of dopamine receptor D4 (DRD4) in psychiatric and neurological disorders is well elucidated. However, the roles of DRD4 in colorectal cancer (CRC) remain unclear. This study observes a significant upregulation of DRD4 expression in clinical samples, which is negatively correlated with patient prognosis. In vitro, overexpression of DRD4 causes a constitutive activation of β-Arrestin2/PP2A/AKT independent of dopamine. Interestingly, this classical signaling pathway is not associated with the phenotype of DRD4-promoted migration and invasion in CRC cells. Instead, DRD4 interacts with transforming growth factor beta receptors (TGFBR1 and TGFBR2) to activate Smad2 phosphorylation and promote Smad2/Smad4 complex nucleus translocation. Then, SNAI1 and JAG1 are transcriptionally activated to induce epithelial-mesenchymal transition and enhance the metastatic potential of CRC. Notably, the COOH-terminal domain is identified as the key intracellular region for the pro-metastatic roles of DRD4. Furthermore, treatment with a TGFBR1 inhibitor combined with a BMP inhibitor effectively counteracts the pro-metastatic effects induced by DRD4 both in vitro and in vivo. In conclusion, these findings uncover an unconventional role for DRD4 beyond its classic function as a neurotransmitter receptor. The intracellular signaling of DRD4 interacting with TGFBR1 can be targeted pharmacologically for CRC therapy.
多巴胺受体D4（DRD4）在精神疾病和神经疾病中的功能及药理学意义已得到充分阐明。然而，DRD4在结直肠癌（CRC）中的作用仍不清楚。本研究观察到临床样本中DRD4表达显著上调，且与患者预后呈负相关。在体外，DRD4的过表达导致β-抑制蛋白2/蛋白磷酸酶2A/蛋白激酶B（β-Arrestin2/PP2A/AKT）的组成性激活，且不依赖多巴胺。有趣的是，这一经典信号通路与DRD4促进CRC细胞迁移和侵袭的表型无关。相反，DRD4与转化生长因子β受体（TGFBR1和TGFBR2）相互作用，激活Smad2磷酸化并促进Smad2/Smad4复合物的核转位。然后，SNAI1和JAG1被转录激活，以诱导上皮-间质转化并增强CRC的转移潜能。值得注意的是，COOH末端结构域被确定为DRD4促转移作用的关键细胞内区域。此外，用TGFBR1抑制剂联合骨形态发生蛋白（BMP）抑制剂进行治疗，可在体外和体内有效对抗DRD4诱导的促转移作用。总之，这些发现揭示了DRD4除作为神经递质受体的经典功能外的非常规作用。DRD4与TGFBR1相互作用的细胞内信号传导可作为CRC治疗的药理学靶点。
