TY - JOUR
T1 - FOXM1 regulates glycolysis and energy production in multiple myeloma
AU - Cheng, Yan
AU - Sun, Fumou
AU - Thornton, Krista
AU - Jing, Xuefang
AU - Dong, Jing
AU - Yun, Grant
AU - Pisano, Michael
AU - Zhan, Fenghuang
AU - Kim, Sung Hoon
AU - Katzenellenbogen, John A.
AU - Katzenellenbogen, Benita S.
AU - Hari, Parameswaran
AU - Janz, Siegfried
N1 - Funding Information:
We wish to acknowledge expert technical assistance from MCW Cancer Center core facility staff, especially Monika Zielonka, Redox and Bioenergetics Shared Resource (CCRBSR); Galina Petrova, Flow Cytometry Shared Resource; and Donna McAllister, Biomedical Imaging Shared Resource. This work was supported by Breast Cancer Research Foundation grants 083 (to BSK) and 084 (to JAK); by NCI R01CA236814, DoD CA180190, Myeloma Crowd Research Initiative and Riney Family Multiple Myeloma Research Program awards (to FZ); and by NCI R01CA151354 (to SJ). Additional support was provided by the MCW Milwaukee William G. Schuett, Jr., Multiple Myeloma Research Endowment.
Funding Information:
We wish to acknowledge expert technical assistance from MCW Cancer Center core facility staff, especially Monika Zielonka, Redox and Bioenergetics Shared Resource (CCRBSR); Galina Petrova, Flow Cytometry Shared Resource; and Donna McAllister, Biomedical Imaging Shared Resource. This work was supported by Breast Cancer Research Foundation grants 083 (to BSK) and 084 (to JAK); by NCI R01CA236814, DoD CA180190, Myeloma Crowd Research Initiative and Riney Family Multiple Myeloma Research Program awards (to FZ); and by NCI R01CA151354 (to SJ). Additional support was provided by the MCW Milwaukee William G. Schuett, Jr., Multiple Myeloma Research Endowment.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/8/5
Y1 - 2022/8/5
N2 - The transcription factor, forkhead box M1 (FOXM1), has been implicated in the natural history and outcome of newly diagnosed high-risk myeloma (HRMM) and relapsed/refractory myeloma (RRMM), but the mechanism with which FOXM1 promotes the growth of neoplastic plasma cells is poorly understood. Here we show that FOXM1 is a positive regulator of myeloma metabolism that greatly impacts the bioenergetic pathways of glycolysis and oxidative phosphorylation (OxPhos). Using FOXM1-deficient myeloma cells as principal experimental model system, we find that FOXM1 increases glucose uptake, lactate output, and oxygen consumption in myeloma. We demonstrate that the novel 1,1-diarylethylene small-compound FOXM1 inhibitor, NB73, suppresses myeloma in cell culture and human-in-mouse xenografts using a mechanism that includes enhanced proteasomal FOXM1 degradation. Consistent with the FOXM1-stabilizing chaperone function of heat shock protein 90 (HSP90), the HSP90 inhibitor, geldanamycin, collaborates with NB73 in slowing down myeloma. These findings define FOXM1 as a key driver of myeloma metabolism and underscore the feasibility of targeting FOXM1 for new approaches to myeloma therapy and prevention.
AB - The transcription factor, forkhead box M1 (FOXM1), has been implicated in the natural history and outcome of newly diagnosed high-risk myeloma (HRMM) and relapsed/refractory myeloma (RRMM), but the mechanism with which FOXM1 promotes the growth of neoplastic plasma cells is poorly understood. Here we show that FOXM1 is a positive regulator of myeloma metabolism that greatly impacts the bioenergetic pathways of glycolysis and oxidative phosphorylation (OxPhos). Using FOXM1-deficient myeloma cells as principal experimental model system, we find that FOXM1 increases glucose uptake, lactate output, and oxygen consumption in myeloma. We demonstrate that the novel 1,1-diarylethylene small-compound FOXM1 inhibitor, NB73, suppresses myeloma in cell culture and human-in-mouse xenografts using a mechanism that includes enhanced proteasomal FOXM1 degradation. Consistent with the FOXM1-stabilizing chaperone function of heat shock protein 90 (HSP90), the HSP90 inhibitor, geldanamycin, collaborates with NB73 in slowing down myeloma. These findings define FOXM1 as a key driver of myeloma metabolism and underscore the feasibility of targeting FOXM1 for new approaches to myeloma therapy and prevention.
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U2 - 10.1038/s41388-022-02398-4
DO - 10.1038/s41388-022-02398-4
M3 - Article
C2 - 35794249
AN - SCOPUS:85133568311
SN - 0950-9232
VL - 41
SP - 3899
EP - 3911
JO - Oncogene
JF - Oncogene
IS - 32
ER -