ArticleBlood advances2020
AKT signaling restrains tumor suppressive functions of FOXO transcription factors and GSK3 kinase in multiple myeloma.
Article in Blood advances, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 34 citations in OpenAlex.
- Calorie restriction modulates the transcription of genes related to stress response and longevity in human muscle: The CALERIE study.Aging cell · 2023Trial
- Ceritinib overcomes proteasome inhibitor resistance in multiple myeloma by suppressing the protein folding response.Haematologica · 2026Article
- PI3K/AKT signaling pathway: molecular crossroads in tumorigenesis and therapeutic innovation.Signal transduction and targeted therapy · 2026Review
- mTORC2 Phosphorylation of GSDME-N Drives Cullin4B-Mediated Proteasomal Degradation to Suppress Pyroptosis and Confer Radioresistance in Small Cell Lung Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Lung adenocarcinoma surfaceome remodeling with EGFR inhibitors uncovers placental alkaline phosphatase as a target for combination therapy.Cell reports. Medicine · 2025Article
- Genomic and insulin-mediated control of metabolic homeostasis by the mosquito ecdysone-induced gene E93.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Elucidating molecularly stratified single agent, and combination, therapeutic strategies targeting MCL1 for lethal prostate cancer.Nature communications · 2025Article
- FoxO1 signaling in B cell malignancies and its therapeutic targeting.FEBS letters · 2025Review
- Forkhead box O proteins in chondrocyte aging and diseases.Journal of orthopaedic translation · 2025Review
- Role of m6A modification in regulating the PI3K/AKT signaling pathway in cancer.Journal of translational medicine · 2023Review
- SETDB1 induces lenalidomide resistance in multiple myeloma cells via epithelial‑mesenchymal transition and PI3K/AKT pathway activation.Experimental and therapeutic medicine · 2023Article
- AKT supports the metabolic fitness of multiple myeloma cells by restricting FOXO activity.Blood advances · 2023Article
- Network pharmacology- and molecular docking-based investigation of the therapeutic potential and mechanism of daucosterol against multiple myeloma.Translational cancer research · 2023Article
- The discrete roles of individual FOXO transcription factor family members in B-cell malignancies.Frontiers in immunology · 2023Review
- 3-Deoxysappanchalcone isolated fromHeliyon · 2022Article
- Review
- FOXO1 mitigates the SMAD3/FOXL2Journal of translational medicine · 2021Article
- Review
- Pathological and Pharmacological Roles of Mitochondrial Reactive Oxygen Species in Malignant Neoplasms: Therapies Involving Chemical Compounds, Natural Products, and Photosensitizers.Molecules (Basel, Switzerland) · 2020Review
- The EGFL7-ITGB3-KLF2 axis enhances survival of multiple myeloma in preclinical models.Blood advances · 2020Article
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The phosphatidylinositide-3 kinases and the downstream mediator AKT drive survival and proliferation of multiple myeloma (MM) cells. AKT signaling is active in MM and has pleiotropic effects; however, the key molecular aspects of AKT dependency in MM are not fully clear. Among the various downstream AKT targets are the Forkhead box O (FOXO) transcription factors (TFs) and glycogen synthase kinase 3 (GSK3), which are negatively regulated by AKT signaling. Here we show that abrogation of AKT signaling in MM cells provokes cell death and cell cycle arrest, which crucially depends on both FOXO TFs and GSK3. Based on gene expression profiling, we defined a FOXO-repressed gene set that has prognostic significance in a large cohort of patients with MM, indicating that AKT-mediated gene activation is associated with inferior overall survival. We further show that AKT signaling stabilizes the antiapoptotic myeloid cell leukemia 1 (MCL1) protein by inhibiting FOXO- and GSK3-mediated MCL1 turnover. In concordance, abrogation of AKT signaling greatly sensitized MM cells for an MCL1-targeting BH3-mimetic, which is currently in clinical development. Taken together, our results indicate that AKT activity is required to restrain the tumor-suppressive functions of FOXO and GSK3, thereby stabilizing the antiapoptotic protein MCL1 in MM. These novel insights into the role of AKT in MM pathogenesis and MCL1 regulation provide opportunities to improve targeted therapy for patients with MM.
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