Choi, E. Y. | Search bioRxiv

bioRxiv2018

The Novel Mnk1/2 Degrader VNLG-152 Potently Inhibits TNBC Tumor Growth and Metastasis

Currently, there are no effective therapies for patients with triple-negative breast cancer (TNBC), an aggressive and highly metastatic disease. Activation of eukaryotic initiation factor 4E (eIF4E) by mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (Mnk1/2) play a critical role in the development, progression and metastasis of TNBC. Herein, we undertook a comprehensive study to evaluate the activity of a first-in-class Mnk1/2 protein degraders, in clinically relevant models of TNBC. These studies enabled us to identify racemic VNLG-152R as the most efficacious Mnk1/2 degrader. By targeting Mnk1/2 protein degradation (activity), VNLG-152R potently inhibited both Mnk-eIF4E and mTORC1 signaling pathways and strongly regulated downstream factors involved in cell cycle regulation, apoptosis, pro-inflammatory cytokines/chemokines secretion, epithelial-mesenchymal transition (EMT) and metastasis. Most importantly, orally bioavailable VNLG-152R exhibited remarkable antitumor and antimetastatic activities against cell line and patient-derived TNBC xenograft models, with no apparent host toxicity. Collectively, these studies demonstrate that targeting Mnk-eIF4E/mTORC1 signaling with a potent Mnk1/2 degrader, VNLG-152R, is a novel therapeutic strategy that can be developed as monotherapy for effective treatment of patients with primary/metastatic TNBC.

cancer biology↗

bioRxiv2017

Glutathione S-transferases: unexpected roles in astrocyte activation and astrocyte-microglia communication during brain inflammation

Astrocytes and microglia play critical roles in brain inflammation, but their mutual regulation is not fully understood. Here we report unexpected roles for glutathione S-transferases (GSTs), particularly GSTM1, in astrocyte activation and astrocyte-mediated enhancement of microglia activation during brain inflammation. We found that astrocyte-specific silencing of GSTM1 expression in the prefrontal cortex (PFC) attenuated microglia activation in brain inflammation induced by systemic injection of lipopolysaccharides (LPS). Gstm1 silencing in astrocytes also attenuated LPS-induced TNF- production by microglia in co-culture. In astrocytes, GSTM1 was required for the activation of nuclear factor-{kappa}B (NF-{kappa}B) and c-Jun N-terminal kinases (JNK) and the production of pro-inflammatory mediators previously implicated in microglia activation, such as granulocyte-macrophage colony-stimulating factor (GM-CSF/CSF2) and chemokine (C-C motif) ligand 2 (CCL2). Similar results were also obtained with GSTT2 both in vitro and in vivo. Thus, our study identified a critical role for GSTs in priming astrocytes and enhancing microglia activation during brain inflammation.\n\nSignificant StatementAstrocytes and microglia play critical roles in brain inflammation, but it is not fully understood how astrocytes regulate microglia activation. Here we report a novel mechanism by which glutathione S-transferases (GSTs), the enzymes for phase II detoxification of xenobiotic metabolism, in astrocytes control microglia activation during brain inflammation. We found that GSTs, particularly GSTM1, regulate the induction of pro-inflammatory mediators via the activation of NF-{kappa}B and JNK in astrocytes. Our studies provide evidence that GST enzymes are active players in brain inflammation and can be targeted to regulate microglia activation.

immunology↗