FOXM1 regulates glycolysis and energy production in multiple myeloma
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 06, 2022
- Source ID
- 10.1038/s41388-022-02398-4
Entities
People
- Benita Katzenellenbogen
- Fenghuang Zhan
- Fumou Sun
- Grant Yun
- Jing Dong
- John Katzenellenbogen
- Krista Thornton
- Michael Pisano
- Parameswaran Hari
- Siegfried Janz
- Sung Hoon Kim
- Xuefang Jing
- Yan Cheng
Organizations
- National Cancer Institute
- The Breast Cancer Research Foundation
- United States Department of Defense
- United States Department of Health and Human Services