Funding tool: Basic research projects
Project-ID: LS19-012
Project start: 01. September 2021
Project end: will follow
Runtime: 36 months / ongoing
Funding amount: € 290.000,00

Brief summary:

At present, multiple myeloma (MM) is an incurable hematological malignancy. In spite of remarkable therapeutic progress 5-year survival rate is still below 50%. Most standard pharmaceutical interventions rely on the application of proteasome inhibitors (PIs). In spite of good initial response rates development of resistance against this type of drugs due to up-regulation of proteasome synthesis is common. Upregulation of proteasome expression upon inhibition of proteasome function is regulated by a highly conserved mechanism that relies on the transcription factor NRF1. Under steady-state conditions ubiquitinated NRF1 is anchored to the endoplasmatic reticulum (ER) and is rapidly degraded by the proteasome. However, upon disruption of proteasome function NRF1 accumulates and is proteolytically cleaved and liberated from the ER membrane by the aspartyl protease DDI2. Cleaved NRF1 translocates to the nucleus where it activates the transcription of almost all proteasomal subunit genes and induces de novo synthesis of proteasome complexes. In solid cancer cells the activation of a second transcription factor, namely NRF3, is regulated analogously to NRF1 by DDI2 in response to yet unidentified cellular signals. Upon cleavage by DDI2, NRF3 translocates to the nucleus to activate downstream targets important for cancer cell proliferation.
Given its important function in NRF1 and NRF3 activation, we hypothesize that inhibiting DDI2 activity will impact on MM cell survival and proliferation. We therefore aim to evaluate DDI2 as potential new drug target in MM treatment (especially in combination with inhibition of proteasome function). To this end we will comprehensively characterize cellular and molecular functions of DDI2 using small hairpin mediated depletion of DDI2 in MM cells. We will also screen for potential DDI2 inhibitors and evaluate their effects on MM growth in cell lines as well as in patient derived cells in the presence or absence of PIs. Since it has been suggested that interaction partners of DDI2 may be required for its catalytic activity, we will additionally characterize protein interactions that may regulate DDI2 activity in vivo.
We are convinced that the knowledge gained within this project will help to get a more comprehensive insight in the regulation and function of DDI2 in MM cells and will provide useful information for developing novel and urgently needed pharmaceutical strategies based on DDI2 inhibition.

Keywords:
Cell Biology, Cancer Research