RT Journal Article
SR Electronic
T1 HSP90 facilitates oncogenic alterations of metabolism in B-cell lymphomas
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.05.29.119925
DO 10.1101/2020.05.29.119925
A1 M. Nieves Calvo-Vidal
A1 Nahuel Zamponi
A1 Jan Krumsiek
A1 Max A. Stockslager
A1 Maria V. Revuelta
A1 Jude M. Phillip
A1 Rossella Marullo
A1 Nikita Kotlov
A1 Jayeshkumar Patel
A1 Shao Ning Yang
A1 Lucy Yang
A1 Tony Taldone
A1 Catherine Thieblemont
A1 John P. Leonard
A1 Peter Martin
A1 Giorgio Inghirami
A1 Gabriela Chiosis
A1 Scott R. Manalis
A1 Leandro Cerchietti
YR 2020
UL http://biorxiv.org/content/early/2020/05/31/2020.05.29.119925.abstract
AB HSP90 is critical for maintenance of the cellular proteostasis. In cancer cells, HSP90 also becomes a nucleating site for the stabilization of multiprotein complexes including signaling pathways and transcription complexes. Here, we described a novel role of HSP90 in the cytosolic compartmentalization of metabolic pathways in proliferating cancer cells. We found that HSP90 assists in the organization of metabolic enzymes into non-membrane-bound functional compartments termed metabosomes. Under experimental conditions that conserved the cellular proteostasis, we demonstrated that the compartmentalizing activity of HSP90 is critical to sustain the coordinated synthesis of multiple metabolites required for energy production, maintenance of the cellular biomass and secretion of immunometabolites. Conversely, inhibition of the nucleating capacity of HSP90 modified the topology of cytosolic metabosomes before protein degradation was apparent decreasing the efficiency of MYC-driven metabolic pathways. Inhibition of HSP90 decreases cancer metabolism in B-cell lymphoma cells and patients providing a novel mechanism of activity for this class of drugs.Competing Interest StatementMemorial Sloan-Kettering Cancer Center holds the intellectual rights to PU-H71. Samus Therapeutics, of which G.C. has partial ownership, has licensed PU-H71. S.R.M. declares that he is a founder and consultant of Travera. N.K. holds shares in BostonGene, Inc. All other authors declare no competing interests