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Transcriptomic profiling of A549 cells in response to Dexamethasone, in the context of GR inhibition based on antagonists as well as a novel GR-PROTAC

ABSTRACT: Glucocorticoid receptors (GR) are important therapeutic targets due to regulation of stress hormones, glucocorticoids (GCs). GCs are altered in neuropsychiatric diseases, but also in cancers and autoimmunes. GR antagonists show some success in modulating GC levels. Yet, occupancy-driven mode of action of the available inhibitors, prevents full inhibition and requires high doses, causing risks in the long-term. To complement the existing tools, we present a highly potent novel catalytic-driven GR degrader, KH-103. We show highly efficient and rapid GR chemical knockdown at nanomolar concentrations. KH-103 is selective for GR, has almost no transcriptional side-effects, and shows higher efficiency in blocking ligand-induced genomic effects compared to other antagonists. Application in cortical cultures, revealed a GR-dependent GC-induced increase in calcium peak-intervals negatable by KH-103 pretreatment. Finally, an in-vivo proof-of-concept application of KH-103 is presented. KH-103 opens new opportunities for more lucid interpretation of GR-functions without disadvantages of genetic-interventions with clinically translatable potentials.

ORGANISM(S): Homo sapiens

PROVIDER: GSE229084 | GEO | 2023/11/12

REPOSITORIES: GEO

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Project description:Glucocorticoids (GCs) are commonly used to treat patients suffering from lymphoid malignancies i.e. leukemia and multiple myeloma. Although GCs are known to be strong inducers of apoptosis in lymphoid cells, the molecular determinants of GC therapy resistance are poorly understood. Although GC treatment triggers important changes in gene expression, few studies have addressed the regulatory role of small regulatory microRNAs (miRNAs) in GC therapy response. Only recently, aberrant microRNA expression has been linked to the development of haematological malignancies and microRNAs have become master regulators of drug resistance. We identified GC inducible mRNA and microRNA transcription profiles in GC sensitive MM1S as compared to GC resistant MM1R cells. Transcriptome analysis revealed that GCs regulate multiple genes involved in cell cycle control, cell organization and cell death in MM1S, which remain unaffected in MM1R cells. Correspondingly, GCs selectively trigger cell death in MM1S but not in MM1R. Out of 32 microRNAs responsive to GC in MM1S cells but not in MM1R cells, mir-150 was identified as the most persistent GC responsive microRNA. Furthermore, Ingenuity Pathways Analysis (IPA) revealed that ectopic transfection of a synthetic mir-150 mimics GC therapy response in MM1S cells, associated with selective changes in mRNA levels of typical GR transactivated and transrepressed target genes. Although mir-150 largely mirrors GC responsive changes in gene expression of the transcription factor Myb, GR chaperone FKBP5, cell cycle modulator proteins (IL23A, SKP2, CDKN1A), chemokine signaling proteins (CXCR4, CX3CR1, CCL3) and mTOR/UPR stress related proteins (DDIT4, TXNIP), we also observed mir-150 selective effects on transcription factors (NR3C2 (MR), Myb, Fos, Jun, C/EBP-beta, IRF4, NFE2L1, ATF3, ATF4,), chaperone molecules HSPA8, HSP90AB1), the sodium channel SCNN1G and UPR stress proteins (TRIB3, DDIT3). Remarkably, mir-150 overexpression was not able to overcome GC therapy resistance, since we could not detect GC like effects of mir-150 in GR (NR3C1) deficient MM1R cells. Altogether GC-inducible mir-150 adds a novel complex layer of regulation for fine tuning GC specific therapeutic responses in multiple myeloma.

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Transcriptomic profiling of A549 cells in response to Dexamethasone, in the context of GR inhibition based on antagonists as well as a novel GR-PROTAC

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