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 - 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.
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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85133568311&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85133568311&partnerID=8YFLogxK
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 -