A5040367009- Cancer, Hypoxia, and Metabolism
- Ubiquitin and proteasome pathways
- PI3K/AKT/mTOR signaling in cancer
- Protein Degradation and Inhibitors
- Multiple Myeloma Research and Treatments
- Cancer-related Molecular Pathways
- Virus-based gene therapy research
- CAR-T cell therapy research
- Histone Deacetylase Inhibitors Research
- Immune Cell Function and Interaction
- RNA modifications and cancer
- interferon and immune responses
- Cancer Research and Treatments
- Autophagy in Disease and Therapy
German Cancer Research Center
2016-2019
Heidelberg University
2016-2019
Svenska Örtmedicinska Institute
2015
Abstract Inhibition of deubiquitinase (DUB) activity is a promising strategy for cancer therapy. VLX1570 an inhibitor proteasome DUB currently in clinical trials relapsed multiple myeloma. Here we show that binds to and inhibits the ubiquitin-specific protease-14 (USP14) vitro, with comparatively weaker inhibitory towards UCHL5 (ubiquitin-C-terminal hydrolase-5). Exposure myeloma cells resulted thermostabilization USP14 at therapeutically relevant concentrations. Transient knockdown or...
Oncogenic human papillomaviruses (HPVs) are closely linked to major malignancies, including cervical and head neck cancers. It is widely assumed that HPV-positive cancer cells under selection pressure continuously express the viral E6/E7 oncogenes, their intracellular p53 levels reconstituted on repression, inhibition phenotypically results in cellular senescence. Here we show hypoxic conditions, as often found subregions of cancers, enable escape from these regulatory principles:...
Natural Killer (NK) cells are innate effector that able to recognize and eliminate tumor through engagement of their surface receptors. NKp30 is a potent activating NK cell receptor elicits efficient cell-mediated target killing. Recently, B7-H6 was identified as expressed ligand for NKp30. Enhanced mRNA levels frequently detected in compared healthy tissues. To gain insight the regulation expression tumors, we investigated transcriptional mechanisms driving by promoter analyses. Using...
Oncogenic HPV types are major human carcinogens. Under hypoxia, HPV-positive cancer cells can repress the viral E6/E7 oncogenes and induce a reversible growth arrest. This response could contribute to therapy resistance, immune evasion, tumor recurrence upon reoxygenation. Here, we uncover evidence that oncogene repression is mediated by hypoxia-induced activation of canonical PI3K/mTORC2/AKT signaling. AKT-dependent downregulation only observed under hypoxia occurs, at least in part,...
// Karin Hoppe-Seyler 1 , Anja Honegger Felicitas Bossler Jasmin Sponagel Julia Bulkescher Claudia Lohrey and Felix Molecular Therapy of Virus-Associated Cancers (F065), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany Correspondence to: Hoppe-Seyler, email: hoppe-seyler@dkfz.de Keywords: human papillomavirus; cervical cancer; hexokinase 2 Received: August 23, 2017 Accepted: October 27, Published: November 15, ABSTRACT Oncogenic types papillomaviruses (HPVs) are major...
Abstract Inhibitors of the proteasome-ubiquitin system have been found to be effective in clinical management multiple myeloma. We here describe compound VLX1570, an optimized lead 19S deubiquitinase inhibitor b- AP15. VLX1570 was shown inhibit enzymatic activities both USP14 and UCHL5 vitro, induce accumulation high molecular weight polyubiquitinated proteins myeloma cells. The showed limited inhibitory activity a panel kinases. induces apoptosis cell death lines at submicromolar...