VCP inhibition induces an unfolded protein response and apoptosis in human acute myeloid leukemia cells
Acute myeloid leukemia (AML) is really a heterogeneous malignancy characterised through the accumulation of undifferentiated white-colored bloodstream cells (blasts) within the bone marrow. Valosin-that contains protein (VCP) is definitely an abundant molecular chaperone that extracts ubiquitylated substrates from protein complexes and cellular compartments just before their degradation through the proteasome. We discovered that management of AML cell lines using the VCP inhibitor CB-5083 results in an amount of ubiquitylated proteins, activation of unfolded protein response (UPR) and apoptosis. Using quantitative mass spectrometry-based proteomics we assessed the results of VCP inhibition around the cellular ubiquitin-modified proteome. We’re able to further reveal that CB-5083 lessens the survival from the AML cell lines THP-1 and MV4-11 inside a concentration-dependent manner, and functions synergistically using the antimetabolite cytarabine and also the BH3-mimetic venetoclax. Finally, we demonstrated that prolonged management of AML cells with CB-5083 results in growth and development of resistance mediated by mutations in VCP.
Taken together, inhibition of VCP results in a lethal unfolded protein response in AML cells and may well be a relevant therapeutic strategy to treat AML, specially when coupled with other drugs. The toxicity and growth and development of resistance possibly limit the utility of VCP inhibitors and need to be further explored in animal models and CB-5083 numerous studies.