作者: Li, Ping ; Fajardo, Abigail ; Yuzhalin, Arseniy E ; Acharya, Sunil ; Saito, Yohei ; Chen, Hao-Nien ; Wei, Yongkun ; Ding, Jingzhen ; Zhang, Chenyu ; Xiao, Yi ; Lorenzi, Philip L ; Zhang, Lin ; Lowery, Frank J ; Fan, Huihui ; Hung, Mien-Chie ; Sun, Yutong ; Duan, Yimin ; Yu, Dihua ; Zhao, Zhongming ; Yuan, Xiangliang ; Huse, Jason T ; Yao, Jun

Brain metastases (BrMs) evade the immune response to develop in the brain, yet the mechanisms of BrM immune evasion remains unclear. This study shows that brain astrocytes induce the overexpression of neuronal-specific cyclin-dependent kinase 5 (Cdk5) in breast cancer-derived BrMs, which facilitates BrM outgrowth in mice. Cdk5-overexpressing BrMs exhibit reduced expression and function of the class I major histocompatibility complex (MHC-I) and antigen-presentation pathway, which are restored by inhibiting Cdk5 genetically or pharmacologically, as evidenced by single-cell RNA sequencing and functional studies. Mechanistically, Cdk5 suppresses MHC-I expression on the cancer cell membrane through the Irf2bp1-Stat1-importin α-Nlrc5 pathway, enabling BrMs to avoid recognition by T cells. Treatment with roscovitine-a clinically applicable Cdk5 inhibitor-alone or combined with immune checkpoint inhibitors, significantly reduces BrM burden and increases tumour-infiltrating functional CD8⁺ lymphocytes in mice. Thus, astrocyte-induced Cdk5 overexpression endorses BrM immune evasion, whereas therapeutically targeting Cdk5 markedly improves the efficacy of immune checkpoint inhibitors and inhibits BrM growth.

2014-09-01·Journal of Molecular Neuroscience3区 · 医学

Hippocampal Glycogen Synthase Kinase 3β is Critical for the Antidepressant Effect of Cyclin-Dependent Kinase 5 Inhibitor in Rats

3区 · 医学

Article

作者: Gang Li ; Lei Wang ; Xing Jin ; Xiangqian Kong ; Ting Liu

Cdk5 is a member of cyclin-dependent kinase (Cdk), a proline-directed serine/threonine kinase, and plays a key role in normal neural development and function. Evidence of previous study showed that chronic inhibition of Cdk5 in hippocampal dentate gyrus (DG) blocked the development of depressive-like symptoms, suggesting that Cdk5 plays a role in development of depression. Forced swim test, novelty-suppressed feeding test, and learned helplessness were used to evaluate the cellular and molecular mechanisms underlying the behavioral regulation of Cdk5 inhibitors in rats. Two Cdk5 inhibitors butyrolactone and roscovitine were used to investigate the possible antidepressant-like actions of Cdk5 blockade and the potential mechanisms. Systemic administration of butyrolactone (200 mg/kg, IP) or roscovitine (100 mg/kg, IP) produced effective antidepressant-like actions. Moreover, infusion (5 mM) of GSK3β activator LY294002 into DG abolished the antidepressant-like actions of butyrolactone and roscovitine, suggesting that inhibition of GSK3β might be involved in the antidepressant effect of Cdk5 inhibitors. Moreover, pretreatment of LY294002 (5 mM) blocked the antidepressant-like effect of butyrolactone and roscovitine in learned helplessness. Additionally, inescapable footshock induced a significant increase of GSK3β activity, while butyrolactone and roscovitine decreased GSK3β activity. In contrast, pretreatment of LY294002 prevented the inhibitory effects of butyrolactone and roscovitine on GSK3β activation. Finally, a specific GSK3β inhibitor, SB216763 (1 ng, DG), demonstrated an effective antidepressant-like action. These findings demonstrate that systemic administration of Cdk5 inhibitors produced antidepressant-like actions and that inhibition of GSK3β is involved in behavioral response of Cdk5 inhibitors.

2010-06-01·European Neuropsychopharmacology3区 · 医学

Previous stress exposure enhances both anxiety-like behaviour and p35 levels in the basolateral amygdala complex: Modulation by midazolam

3区 · 医学

Article

作者: Gabriela Paglini ; Elena Anahi Bignante ; Victor Alejandro Molina

Stress exposure induces long lasting neurobiological changes in selected brain areas, which could be associated with the emergence of negative emotional responses. In the present study, previously restrained animals exhibited excessive anxiety one day later in the elevated plus maze. We explore whether stress exposure affects the expression levels of cyclin-dependent kinase 5 (Cdk5) and of its activator protein p35, in diverse amygdaloid nuclei. Stress exposure enhanced p35 levels selectively in the basolateral amygdala (BLA). This up-regulation might be functionally associated with the occurrence of exaggerated anxiety since such emotional response was selectively reversed by an intra-BLA infusion of olomoucine, a Cdk5 inhibitor, 15 min prior to the restraint session. Moreover, pre-treatment with midazolam, a benzodiazepine ligand, not only prevented the excessive anxiety but also attenuated the p35 increase in the BLA of stressed rats. In conclusion, we suggest a pivotal role of the Cdk5/p35 complex, specifically in BLA in the excessive anxiety induced by a previous stressful experience.

100 项与 CDK5 抑制肽相关的药物交易

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