2. Academic Validation
  3. The molecular network of the proteasome machinery inhibition response is orchestrated by HSP70, revealing vulnerabilities in cancer cells

The molecular network of the proteasome machinery inhibition response is orchestrated by HSP70, revealing vulnerabilities in cancer cells

  • Cell Rep. 2022 Sep 27;40(13):111428. doi: 10.1016/j.celrep.2022.111428.
Magdalena Oroń 1,  Marcin Grochowski 1,  Akanksha Jaiswar 1,  Justyna Legierska 1,  Kamil Jastrzębski 2,  Magdalena Nowak-Niezgoda 3,  Małgorzata Kołos 3,  Wojciech Kaźmierczak 4,  Tomasz Olesiński 4,  Małgorzata Lenarcik 4,  Magdalena Cybulska 4,  Michał Mikula 4,  Alicja Żylicz 2,  Marta Miączyńska 2,  Katharina Zettl 5,  Jacek R Wiśniewski 5,  Dawid Walerych 6
Affiliations

Affiliations

  • 1 Mossakowski Medical Research Institute PAS, Warsaw, Poland.
  • 2 International Institute of Molecular and Cell Biology, Warsaw, Poland.
  • 3 Central Clinical Hospital of Ministry of Interior and Administration, Warsaw, Poland.
  • 4 National Center of Oncology, Warsaw, Poland.
  • 5 Max Planck Institute of Biochemistry, Martinsried, Germany.
  • 6 Mossakowski Medical Research Institute PAS, Warsaw, Poland. Electronic address: dwalerych@imdik.pan.pl.
PMID: 36170818 DOI: 10.1016/j.celrep.2022.111428
Abstract

Proteasome machinery is a major proteostasis control system in human cells, actively compensated upon its inhibition. To understand this compensation, we compared global protein landscapes upon the Proteasome inhibition with carfilzomib, in normal fibroblasts, cells of multiple myeloma, and cancers of lung, colon, and pancreas. Molecular chaperones, Autophagy, and endocytosis-related proteins are the most prominent vulnerabilities in combination with carfilzomib, while targeting of the HSP70 family chaperones HSPA1A/B most specifically sensitizes Cancer cells to the Proteasome inhibition. This suggests a central role of HSP70 in the suppression of the Proteasome downregulation, allowing to identify pathways impinging on HSP70 upon the Proteasome inhibition. HSPA1A/B indeed controls proteasome-inhibition-induced Autophagy, unfolded protein response, and endocytic flux, and directly chaperones the Proteasome machinery. However, it does not control the NRF1/2-driven Proteasome subunit transcriptional bounce-back. Consequently, targeting of NRF1 proves effective in decreasing the viability of Cancer cells with the inhibited Proteasome and HSP70.

Keywords

CP: Cancer; HSP70; NFR2; NRF1; autophagy; cancer; carfilzomib; endocytosis; proteasome; proteomics; unfolded protein response.

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