GSE184029
HSP70-driven molecular response to the proteasome machinery inhibition is a vulnerability in cancer
In this study we employed a label-free global proteomics approach, with a sensitivity of over 10k quantified proteins per sample, to determine contributions of different compensatory mechanisms upon the proteasome inhibition with carfilzomib - in cells of multiple myeloma, normal fibroblasts and cancers of lung, colon and pancreas. We identified several responding pathways, while the main HSP70 family stress inducible molecular chaperones HSPA1A and HSPA1B (often addressed jointly as HSPA1A/B or simply “Hsp70”, due to nearly identical protein sequences) were the most universal proteasome inhibition responders in proteomes of all the studied cell types. Further overlap of differential proteomics with RNA-seq analysis obtained at the same condions (DMSO control vs carfilzomib treatment) and a subsequent validation showed that the proteasome inhibition-dependent induction of HSPA1A/B and other chaperone proteins in cancer cells is in fact transcription-driven. Overall design: Cell lines were either treated with carfilzomib (C) for 24h at concentrations at the IC50 of proteasome activity, or with DMSO (D) as a control, in biological triplicates (numbers 1-3). Total RNA was exracted from cells and subjected to mRNA sequencing.