Data from: PYCR1 inhibition in bone marrow stromal cells enhances bortezomib sensitivity in multiple myeloma cells by altering their metabolism

Despite significant advancements, multiple myeloma (MM) remains incurable,
largely due to drug resistance. Our previous research has demonstrated
that proline metabolism plays a role in MM progression and that inhibiting
PYCR1, the final enzyme in proline synthesis, enhances bortezomib
sensitivity in MM cells. Given the high expression of PYCR1 in bone marrow
stromal cells (BMSC), we sought to investigate the effects of PYCR1
inhibition in BMSC and its indirect influence on MM cell metabolism and
viability. Culturing MM cells in conditioned medium (CM) of PYCR1-silenced
BMSC significantly impaired oxidative phosphorylation and sensitized MM
cells to bortezomib. Analysis of the CM secretome revealed a reduction in
activin A release. Proline and activin A supplementation were able to
counteract MM sensitivity to bortezomib. Combination therapy of the PYCR1
inhibitor pargyline and bortezomib reduced tumour load in a 3D model and
reduced serum activin A levels in 5TGM1-bearing mice. This study
demonstrates the contribution of stromal cell metabolism to MM
progression. Inhibiting PYCR1 in BMSC leads to less activin A release,
limits oxidative phosphorylation in MM cells and enhances bortezomib
efficacy.