PCNA has specific functions in regulation of metabolism in haematological cells

ABSTRACT: PCNA´s essential roles in DNA replication and repair are well established, while it’s recently discovered non-canonical roles in cellular signalling and regulation of metabolism are less explored. Recent data has indicated that PCNA has a specific non-canonical role in cells of haematological origin. In the present study we have explored this further at the system level by extensive protein-, gene expression, and metabolite profiling combined with integrated pathway analysis and by 13C label experimentation, Here we show that impairing PCNA´s scaffold functions led to massive changes in cellular signalling, but more importantly, a strong reduction in glycolytic metabolites and nucleoside phosphate pools in haematological cancer cell lines was detected, including multiple myeloma cells and acute myelogen leukaemia cells. This was not observed in cell lines from solid tissues such as kidney, bladder and prostate, nor in primary monocytes. Lipopolysaccharide (LPS) stimulated monocytes on the other hand, responded to treatment similarly to the haematological cancer cells, suggesting that cellular stress is an important factor for the response to the APIM-peptide in haematological cells. Integrated Pathway analysis of the metabolite and protein datasets revealed that protein ubiquitination and antigen presentation pathways are affected in haematopoietic cancer cells upon treatment. Focusing on one multiple myeloma cell line we further verified these trends by gene-expression and show that the consequences of reduced central carbon metabolite pools and energy charge is impaired redox and HIF1A regulation. Altogether, our data suggests that PCNA has an important role in regulation of cytoplasmic stress via regulation of central carbon metabolism in haematological cells that can be targeted in cancer treatment.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Embryo, Kidney Epithelial Cell

SUBMITTER: Animesh Sharma  

LAB HEAD: Marit Otterlei

PROVIDER: PXD017474 | Pride | 2023-03-10

REPOSITORIES: pride