Background. Breast and ovarian cancers are common malignancies among women, contributing to a significant disease burden, and are characterized by a high level of genomic instability, owing to the failure of homologous recombination repair (HRR). Pharmacological inhibition of poly(ADP-ribose) polymerase (PARP) could elicit the synthetic lethal effect of tumor cells in patients with homologous recombination deficiency, ultimately achieving a favorable clinical benefit. However, primary and acquired resistance remain the greatest hurdle, limiting the efficacy of PARP inhibitors; thus, strategies conferring or augmenting tumor cell sensitivity to PARP inhibitors are urgently required. Methods. Our RNA-seq data of niraparib-treated and -untreated tumor cells were analyzed by R language. Gene Set Enrichment Analysis (GSEA) was applied to assess the biological functions of GTP cyclohydrolase 1 (GCH1). Quantitative real-time PCR, Western blotting, and immunofluorescence were applied to confirm the upregulation of GCH1 upon niraparib treatment at transcriptional and translational levels. Immunohistochemistry of patient-derived xenograft (PDX)-derived tissue sections further validated that niraparib increased GCH1 expression. Tumor cell apoptosis was detected by flow cytometry, while the superiority of the combination strategy was confirmed in the PDX model. Results. The expression of GCH1 was aberrantly enriched in breast and ovarian cancers and increased after niraparib treatment via JAK-STAT signaling. GCH1 was also demonstrated to be associated with the HRR pathway. Subsequently, the enhancement of the tumor-killing effect of PARP inhibitors induced by GCH1 suppression using siRNA and GCH1 inhibitor was validated by flow cytometry in vitro. Finally, using the PDX model, we further demonstrated that GCH1 inhibitors markedly potentiated PARP inhibitors’ antitumor efficacy in vivo. Conclusion. Our results illustrated that PARP inhibitors promote GCH1 expression via the JAK-STAT pathway. We also elucidated the potential relationship between GCH1 and the homologous recombination repair pathway and proposed a combination regimen of GCH1 suppression with PARP inhibitors in breast and ovarian cancers.

15 Dec 2020·Proceedings of the National Academy of SciencesQ1 · CROSS-FIELD

A hybrid approach reveals the allosteric regulation of GTP cyclohydrolase I

Q1 · CROSS-FIELD

Article

Author: Kaltwasser, Susann ; Prinz, Simone ; Mills, Deryck J. ; Nar, Herbert ; Weixler, Lisa ; Vonck, Janet ; Rübbelke, Martin ; Bauer, Margit ; Meinecke, Robert ; Ebenhoch, Rebecca ; Reinert, Dirk ; Zeeb, Markus

SignificanceWe present a comprehensive structural study, which shows the human GCH1 and GCH1−GFRP complexes in all states (apo, ligand bound, partially and fully inhibited). We observed local rearrangements in the allosteric pocket upon BH4 binding, which result in drastic changes in the quaternary structure of the enzyme leading to a more compact, tense form in the inhibited protein. Inhibition of the enzymatic activity is not a result of hindrance of substrate binding, but rather a consequence of accelerated substrate binding kinetics as shown by STD-NMR and site-directed mutagenesis. We propose a dissociation rate-controlled mechanism of allosteric, noncompetitive inhibition, which could stimulate further research toward the development of GCH1 inhibitors to treat neuropathic and inflammatory pain disorders.

01 Dec 2019·Biochemical and Biophysical Research CommunicationsQ3 · BIOLOGY

Sodium Tanshinone IIA sulfonate improves post-ischemic angiogenesis in hyperglycemia

Q3 · BIOLOGY

Article

Author: Chen, Lingdan ; Wang, Jian ; Wang, Tao ; Yuan, Mingjie ; Peng, Bin ; Lu, Wenju ; He, Wenjun ; Wang, Neng

BACKGROUNDDiabetes is a strong risk factor of peripheral arterial disease (PAD), and also leads to impaired perfusion recovery in the ischemic limb, which eventually results in poor outcomes in PAD patients. Sodium Tanshinone IIA Sulfonate (STS), a monomer from herbs, has been shown to improve the outcomes in a variety of ischemic disease including myocardial infarction. However, the effects of STS treatment in PAD is not known.METHODS AND RESULTSUnilateral femoral artery was ligated in mice as experimental PAD models, STS treatment improved perfusion recovery, increased capillary densities, decreased reactive oxygen species (ROS) level and microRNA-133a (miR-133a) expression in the ischemic hindlimb in diabetic mice; however, STS did not change perfusion recovery in non-diabetic C57BL/6 mice. Ischemic muscle tissue from diabetic mice was harvested 7 days after femoral ligation for biochemical test, STS resulted in reduced malondialdehyde (MDA), and increased GTP cyclohydrolase 1 (GCH1) and cyclic guanine monophosphate (cGMP) levels. In addition, STS treatment increased miR-133a expression in endothelial cells isolated from ischemic muscle tissue of diabetic mice. In endothelial cells cultured in high glucose medium, STS increased tube formation and nitric oxide (NO) production, and reduced cellular ROS level and miR-133a expression under simulated ischemic condition. In addition, GCH1 inhibitor or miR-133a overexpression using exogenous microRNA mimic blunted STS-induced angiogenic effects and ROS neutralization in cultured endothelial cells under hyperglycemic and hypoxic conditions.CONCLUSIONThese findings demonstrate STS improves angiogenesis via inhibiting miR-133a expression and increasing GCH-1 protein levels in experimental PAD with diabetes.

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