Journal article
The mitochondrial pyruvate carrier complex potentiates the efficacy of proteasome inhibitors in multiple myeloma
Blood advances, Vol.7(14), pp.3485-3500
07/13/2023
DOI: 10.1182/bloodadvances.2022008345
PMCID: PMC10362273
PMID: 36920785
Abstract
Multiple myeloma (MM) is a hematological malignancy that emerges from antibody-producing plasma B cells. Proteasome inhibitors, including the FDA-approved bortezomib (BTZ) and carfilzomib (CFZ), are frequently used for the treatment of MM patients. Still, a significant proportion of MM patients are refractory or develop resistance to this class of inhibitors, which represents a significant challenge in the clinic. Thus, identifying factors that determine the potency of proteasome inhibitors in MM is of paramount importance to bolster their efficacy in the clinic. Using genome-wide CRISPR-based screening, we identified a subunit of the mitochondrial pyruvate carrier (MPC) complex, MPC1, as a common modulator of BTZ response in two distinct human MM cell lines in vitro. We noticed that CRISPR-mediated deletion or pharmacological inhibition of the MPC complex enhanced BTZ/CFZ-induced MM cell death with minimal impact on cell cycle progression. In fact, targeting the MPC complex compromised the bioenergetic capacity of MM cells, which is accompanied by a reduced proteasomal activity, thereby exacerbating BTZ-induced cytotoxicity in vitro. Importantly, we observed that the RNA expression levels of several players in pyruvate metabolism were altered in advanced stages of MM wherein they correlated with poor prognosis for MM patients. Collectively, this study highlights the importance of the MPC complex for the survival of MM cells and their responses to proteasome inhibitors. These findings establish mitochondrial pyruvate metabolism as a potential target for the treatment of MM, and a hitherto unappreciated strategy to increase the efficacy of proteasome inhibitors in the clinic.
Details
- Title: Subtitle
- The mitochondrial pyruvate carrier complex potentiates the efficacy of proteasome inhibitors in multiple myeloma
- Creators
- Steven Findlay - Lady Davis Institute, Montreal, CanadaRemya Nair - Emory UniversityRonald A Merrill - University of Iowa, Iowa City, Iowa, United StatesZafir Kaiser - McGill UniversityAlexandre Cajelot - Lady Davis Institute, Montreal, CanadaZahra Aryanpour - Lady Davis Institute, Montreal, CanadaJohn Heath - Lady Davis Institute, Montreal, CanadaCatherine St-Louis - University of OttawaDavid Papadopoli - Lady Davis Institute, Montreal, CanadaIvan Topisirovic - Lady Davis Institute, Montreal, CanadaJulie St-Pierre - University of OttawaMichael Sebag - McGill UniversityAparna H Kesarwala - Emory UniversityLaura Hulea - Hôpital Maisonneuve-RosemontEric B Taylor - University of Iowa, Iowa City, Iowa, United StatesMala Shanmugam - Emory UniversityAlexandre Orthwein - Emory and Henry College
- Resource Type
- Journal article
- Publication Details
- Blood advances, Vol.7(14), pp.3485-3500
- DOI
- 10.1182/bloodadvances.2022008345
- PMID
- 36920785
- PMCID
- PMC10362273
- NLM abbreviation
- Blood Adv
- ISSN
- 2473-9529
- eISSN
- 2473-9537
- Grant note
- R01 DK104998 / NIDDK NIH HHS
- Language
- English
- Electronic publication date
- 03/15/2023
- Date published
- 07/13/2023
- Academic Unit
- Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984384758902771
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