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Targeting arginase-1 exerts antitumor effects in multiple myeloma and mitigates bortezomib-induced cardiotoxicity.

ABSTRACT: Multiple myeloma (MM) remains an incurable malignancy of plasma cells despite constantly evolving therapeutic approaches including various types of immunotherapy. Increased arginase activity has been associated with potent suppression of T-cell immune responses in different types of cancer. Here, we investigated the role of arginase 1 (ARG1) in Vκ*MYC model of MM in mice. ARG1 expression in myeloid cells correlated with tumor progression and was accompanied by a systemic drop in ʟ-arginine levels. In MM-bearing mice antigen-induced proliferation of adoptively transferred T-cells was strongly suppressed and T-cell proliferation was restored by pharmacological arginase inhibition. Progression of Vκ*MYC tumors was significantly delayed in mice with myeloid-specific ARG1 deletion. Arginase inhibition effectively inhibited tumor progression although it failed to augment anti-myeloma effects of bortezomib. However, arginase inhibitor completely prevented development of bortezomib-induced cardiotoxicity in mice. Altogether, these findings indicate that arginase inhibitors could be further tested as a complementary strategy in multiple myeloma to mitigate adverse cardiac events without compromising antitumor efficacy of proteasome inhibitors.

SUBMITTER: Ramji K

PROVIDER: S-EPMC9668840 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Targeting arginase-1 exerts antitumor effects in multiple myeloma and mitigates bortezomib-induced cardiotoxicity.

Ramji Kavita K Grzywa Tomasz M TM Sosnowska Anna A Paterek Aleksandra A Okninska Marta M Pilch Zofia Z Barankiewicz Joanna J Garbicz Filip F Borg Katarzyna K Bany-Laszewicz Urszula U Zerrouqi Abdesamad A Pyrzynska Beata B Rodziewicz-Lurzynska Anna A Papiernik Diana D Sklepkiewicz Piotr P Kedzierska Hanna H Staruch Adam A Sadowski Radoslaw R Ciepiela Olga O Lech-Maranda Ewa E Juszczynski Przemyslaw P Mackiewicz Urszula U Maczewski Michal M Nowis Dominika D Golab Jakub J

Scientific reports 20221116 1

Multiple myeloma (MM) remains an incurable malignancy of plasma cells despite constantly evolving therapeutic approaches including various types of immunotherapy. Increased arginase activity has been associated with potent suppression of T-cell immune responses in different types of cancer. Here, we investigated the role of arginase 1 (ARG1) in Vκ*MYC model of MM in mice. ARG1 expression in myeloid cells correlated with tumor progression and was accompanied by a systemic drop in ʟ-arginine level ...[more]

PMID: 36385153

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Project description:BackgroundEnolase 1 (ENO1) is a conserved glycolytic enzyme that regulates glycolysis metabolism. However, its role beyond glycolysis in the pathophysiology of multiple myeloma (MM) remains largely elusive. Herein, this study aimed to elucidate the function of ENO1 in MM, particularly its impact on mitophagy under bortezomib-induced apoptosis.MethodsThe bone marrow of clinical MM patients and healthy normal donors was used to compare the expression level of ENO1. Using online databases, we conducted an analysis to examine the correlation between ENO1 expression and both clinicopathological characteristics and patient outcomes. To investigate the biological functions of ENO1 in MM and the underlying molecular mechanisms involved, we conducted the following experiment: construction of a subcutaneous graft tumor model, co-immunoprecipitation, western blot, quantitative real-time polymerase chain reaction, immunohistochemistry, flow cytometry, and cell functional assays.ResultsENO1 was identified as an unfavorable prognostic factor in MM. ENO1 knockdown suppresses tumorigenicity and causes cell cycle arrest. Inhibition of ENO1-regulated mitophagy sensitizes tumor cells to apoptosis. ENO1 enhanced the stability of the YWHAZ protein by increasing the acetylation of lysine in YWHAZ while antagonizing its ubiquitination, which in turn promoted mitophagy. HDAC6 mediates the deacetylation of YWHAZ by deacetylating the K138 site of YWHAZ. Inhibition of HDAC6 increased YWHAZ acetylation and decreased YWHAZ ubiquitination. Furthermore, combination treatment with bortezomib and pharmaceutical agents targeting ENO1 has synergistic anti-MM effects both in vivo and in vitro.ConclusionOur data suggest that ENO1 promotes MM tumorigenesis and progression. ENO1 activates mitophagy by promoting the stability of YWHAZ and inhibits apoptosis and thus, leads to the drug resistance. ENO1-dependent mitophagy promotes MM proliferation and suppresses the level of bortezomib-induced apoptosis. Inhibition of ENO1 may represent a potential strategy to reverse the resistance of MM to bortezomib.

Dataset Information

Targeting arginase-1 exerts antitumor effects in multiple myeloma and mitigates bortezomib-induced cardiotoxicity.

Publications

Targeting arginase-1 exerts antitumor effects in multiple myeloma and mitigates bortezomib-induced cardiotoxicity.

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