AP-1 inhibitor induces ferroptosis via the PI3K/AKT pathway in multiple myeloma cells
Open accessAbstract
Multiple myeloma (MM) is an incurable malignancy of plasma cells that is sensitive to T-5224, an AP-1 inhibitor. Previous study indicated that T-5224 inhibits proliferation and induces apoptosis in MM cells. However, the high mortality cannot be fully explained. To date, no studies have investigated ferroptosis induced by T-5224 in MM. Therefore, we further investigated the mechanism by which T-5224 kills MM cells. We observed that T-5224 exhibits antimyeloma properties both in vitro and in vivo. T-5224-induced MM cell death was reversed by the ferroptosis-specific inhibitor ferropstatin-1 (Fer-1). The protein levels of the key ferroptosis regulators GPX4 and SLC7A11 were decreased by T-5224 in MM cells. Furthermore, T-5224 reduced the phosphorylation of PI3K and AKT signaling pathway components, ultimately causing MM cell death. Using 740 Y-P, a PI3K activator, and Fer-1, a ferroptosis inhibitor, we discovered that T-5224 induces ferroptosis through the PI3K/AKT pathway. Bortezomib (BTZ), an FDA-approved drug for MM treatment, can be administered in combination with other agents. We evaluated the synergistic effect of BTZ combined with AP-1 inhibitors on MM in vivo. Our findings provide a better theoretical basis for the potential mechanism of T-5224 and a new perspective on MM treatment.
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Several transcription factors including AP-1, CREB, ATF4, and NRF2 have been shown to regulate either directly or indirectly GPX4 levels in different cellular contexts.
“Several transcription factors including AP-1 (60, 61), CREB (62, 63), ATF4 (64), and NRF2 (45, 65, 66) have been shown to regulate either directly or indirectly GPX4 levels in different cellular contexts.”
From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [61]
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- Authors
- Tang, S., Liu, J., Li, F., Yan, Y., Long, X., & Fu, Y.
- Affiliations
- Central South University (CN)
- Corresponding author
- Fu, Yunfeng
- Venue
- Heliyon
- Publisher
- Elsevier BV
- Published
- 2024-07
- Volume
- 10
- Issue
- 14
- Pages
- e34397
- ISSN
- 2405-8440 (ISSN-L)
- PMC
- PMC11298940
- OpenAlex
- W4400486484
- Cited by
- 13
- References
- 46
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 4
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Heliyon (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Natural Science Foundation of China (81870166)
- Hunan Provincial Natural Science Foundation (2022JJ30885)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- multiple myeloma, ferroptosis, T-5224, PI3K/Akt signaling, GPX4, SLC7A11, bortezomib combination therapy, drug synergy, plasma cell malignancy
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