PLK1 inhibitors are emerging anticancer agents that are being tested as monotherapy and combination therapies for various cancers. Although PLK1 inhibition in experimental models has shown potent antitumor effects, translation to the clinic has been hampered by low antitumor activity and tumor relapse. Here, we report the identification of mitochondrial protein signatures that determine the sensitivity to approaches targeting PLK1 in human melanoma cell lines. In response to PLK1 inhibition or gene silencing, resistant cells adopt a pro-inflammatory and dedifferentiated phenotype, whereas sensitive cells undergo apoptosis. Mitochondrial DNA depletion and silencing of the ABCD1 transporter sensitize cells to PLK1 inhibition and attenuate the associated pro-inflammatory response. We also found that nonselective inhibitors of the p90 ribosomal S6 kinase (RSK) exert their antiproliferative and pro-inflammatory effects via PLK1 inhibition. Specific inhibition of RSK, on the other hand, is anti-inflammatory and promotes a program of antigen presentation. This study reveals the overlooked effects of PLK1 on phenotype switching and suggests that mitochondrial precision medicine can help improve the response to targeted therapies.

2025-03-01·Ecotoxicology and Environmental Safety

Maternal exposure to polystyrene nanoplastics induces sex-specific kidney injury in offspring

Article

作者: Wang, Qiuming ; Wang, Li ; Liu, Kan ; Wu, Haiying ; Niu, Leilei ; Chen, Xiuli ; Li, Ranhong

Maternal exposure to polystyrene nanoplastics (PS-NPs) during pregnancy and lactation has been linked to adverse effects on offspring kidney development, with sex-specific outcomes. This study investigated the impact of maternal PS-NPs exposure on kidney weight, histology, transcriptomics, and functional pathways in offspring mice. Offspring exposed to PS-NPs exhibited significantly lower body weight (P < 0.05) and an increased kidney-to-body weight ratio (P < 0.05), particularly in males. Histological analysis revealed a reduction in glomerular number in PS-NP-treated groups. Transcriptome profiling identified 758 differentially expressed genes (DEGs) in male and 101 DEGs in female offspring, with males showing a more pronounced alteration in gene expression. KEGG pathway enrichment highlighted disruptions in immune response, cell cycle regulation, and metabolism, with males exhibiting more extensive pathway changes than females. Additionally, PS-NPs exposure increased renal fibrosis (P < 0.05), with molecular analyses confirming sex-specific gene expression patterns linked to fibrosis and apoptosis. Immunohistochemical analysis revealed enhanced macrophage infiltration and cleaved caspase-3 expression, indicating heightened immune and apoptotic responses in males. Further investigation identified small molecules BI-D1870 and Resatorvid as potential therapeutic agents, reducing fibrosis, inflammation, and apoptosis in male and female offspring, respectively. These findings demonstrate that maternal PS-NPs exposure induces sex-specific kidney injury in offspring, disrupting key biological processes and pathways. The study underscores the need for targeted therapeutic interventions to mitigate these effects and highlights potential compounds for future treatment.

2024-10-01·Neuroscience

Ribosomal S6 kinase signaling regulates neuronal viability during development and confers resistance to excitotoxic cell death in mature neurons

Article

作者: Georgette Ang, Pia ; Obrietan, Karl ; Karelina, Kate ; Horning, Paul ; Hoyt, Kari R

The Ribosomal S6 Kinase (RSK) family of serine/threonine kinases function as key downstream effectors of the MAPK signaling cascade. In the nervous system, RSK signaling plays crucial roles in neuronal development and contributes to activity-dependent neuronal plasticity. This study examined the role of RSK signaling in cell viability during neuronal development and in neuroprotection in the mature nervous system. Using neuronal cell-culture-based profiling, we found that suppressing RSK signaling led to significant cell death in developing primary neuronal cultures. To this end, treatment with the RSK inhibitors BiD1870 or SL0101 on the first day of culturing resulted in over 80% cell death. In contrast, more mature cultures showed attenuated cell death upon RSK inhibition. Inhibition of RSK signaling during early neuronal development also disrupted neurite outgrowth and cell growth. In maturing hippocampal explant cultures, treatment with BiD1870 had minimal effects on cell viability, but led to a striking augmentation of NMDA-induced cell death. Finally, we used the endothelin 1 (ET-1) model of ischemia to examine the neuroprotective effects of RSK signaling in the mature hippocampus in vivo. Notably, in the absence of RSK inhibition, the granule cell layer (GCL) was resistant to the effects of ET-1; However, disruption of RSK signaling (via the microinjection of BiD1870) prior to ET-1 injection triggered cell death within the GCL, thus indicating a neuroprotective role for RSK signaling in the mature nervous system. Together these data reveal distinct, developmentally-defined, roles for RSK signaling in the nervous system.

100 项与 BI-D1870 相关的药物交易

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