Cellular senescence-driven transcriptional reprogramming of the MAFB/NOTCH3 axis activates the PI3K/AKT pathway and promotes osteosarcoma progression
Osteosarcoma is the most common primary malignancy of bones and primarily occurs in adolescents and young adults. However, a second smaller peak of osteosarcoma incidence was reported in the elderly aged more than 60. Elderly patients with osteosarcoma exhibit different characteristics compared to y...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
KeAi Communications Co., Ltd.
2024-03-01
|
| Series: | Genes and Diseases |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352304223000806 |
| _version_ | 1797731041308311552 |
|---|---|
| author | Zhenhao Zhang Doudou Jing Baijun Xuan Zhicai Zhang Wei Wu Zengwu Shao |
| author_facet | Zhenhao Zhang Doudou Jing Baijun Xuan Zhicai Zhang Wei Wu Zengwu Shao |
| author_sort | Zhenhao Zhang |
| collection | DOAJ |
| description | Osteosarcoma is the most common primary malignancy of bones and primarily occurs in adolescents and young adults. However, a second smaller peak of osteosarcoma incidence was reported in the elderly aged more than 60. Elderly patients with osteosarcoma exhibit different characteristics compared to young patients, which usually results in a poor prognosis. The mechanism underlying osteosarcoma development in elderly patients is intriguing and of significant value in clinical applications. Senescent cells can accelerate tumor progression by metabolic reprogramming. Recent research has shown that methylmalonic acid (MMA) was significantly up-regulated in the serum of older individuals and played a central role in the development of aggressive characteristics. We found that the significant accumulation of MMA in elderly patients imparted proliferative potential to osteosarcoma cells. The expression of MAFB was excessively up-regulated in osteosarcoma specimens and was further enhanced in response to MMA accumulation as the patient aged. Specifically, we first confirmed a novel molecular mechanism between cellular senescence and cancer, in which the MMA-driven transcriptional reprogramming of the MAFB-NOTCH3 axis accelerated osteosarcoma progression via the activation of PI3K-AKT pathways. Moreover, the down-regulation of the MAFB-NOTCH3 axis increased the sensitivity and effect of AKT inhibitors in osteosarcoma through significant inhibition of AKT phosphorylation. In conclusion, we confirmed that MAFB is a novel age-dependent biomarker for osteosarcoma, and targeting the MAFB-NOTCH3 axis in combination with AKT inhibition can serve as a novel therapeutic strategy for elderly patients with osteosarcoma in experimental and clinical trials. |
| first_indexed | 2024-03-12T11:53:02Z |
| format | Article |
| id | doaj.art-b89b2ae381ab4cbb81b070b76dca61c8 |
| institution | Directory Open Access Journal |
| issn | 2352-3042 |
| language | English |
| last_indexed | 2024-03-12T11:53:02Z |
| publishDate | 2024-03-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Genes and Diseases |
| spelling | doaj.art-b89b2ae381ab4cbb81b070b76dca61c82023-08-31T05:03:02ZengKeAi Communications Co., Ltd.Genes and Diseases2352-30422024-03-01112952963Cellular senescence-driven transcriptional reprogramming of the MAFB/NOTCH3 axis activates the PI3K/AKT pathway and promotes osteosarcoma progressionZhenhao Zhang0Doudou Jing1Baijun Xuan2Zhicai Zhang3Wei Wu4Zengwu Shao5Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, ChinaDepartment of Orthopedics, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, ChinaDepartment of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, ChinaDepartment of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Corresponding author.Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Corresponding author.Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Corresponding author.Osteosarcoma is the most common primary malignancy of bones and primarily occurs in adolescents and young adults. However, a second smaller peak of osteosarcoma incidence was reported in the elderly aged more than 60. Elderly patients with osteosarcoma exhibit different characteristics compared to young patients, which usually results in a poor prognosis. The mechanism underlying osteosarcoma development in elderly patients is intriguing and of significant value in clinical applications. Senescent cells can accelerate tumor progression by metabolic reprogramming. Recent research has shown that methylmalonic acid (MMA) was significantly up-regulated in the serum of older individuals and played a central role in the development of aggressive characteristics. We found that the significant accumulation of MMA in elderly patients imparted proliferative potential to osteosarcoma cells. The expression of MAFB was excessively up-regulated in osteosarcoma specimens and was further enhanced in response to MMA accumulation as the patient aged. Specifically, we first confirmed a novel molecular mechanism between cellular senescence and cancer, in which the MMA-driven transcriptional reprogramming of the MAFB-NOTCH3 axis accelerated osteosarcoma progression via the activation of PI3K-AKT pathways. Moreover, the down-regulation of the MAFB-NOTCH3 axis increased the sensitivity and effect of AKT inhibitors in osteosarcoma through significant inhibition of AKT phosphorylation. In conclusion, we confirmed that MAFB is a novel age-dependent biomarker for osteosarcoma, and targeting the MAFB-NOTCH3 axis in combination with AKT inhibition can serve as a novel therapeutic strategy for elderly patients with osteosarcoma in experimental and clinical trials.http://www.sciencedirect.com/science/article/pii/S2352304223000806Cellular senescenceElderly patientsMAFB-NOTCH3axisMethylmalonic acidOsteosarcomaPI3K-AKTpathway |
| spellingShingle | Zhenhao Zhang Doudou Jing Baijun Xuan Zhicai Zhang Wei Wu Zengwu Shao Cellular senescence-driven transcriptional reprogramming of the MAFB/NOTCH3 axis activates the PI3K/AKT pathway and promotes osteosarcoma progression Genes and Diseases Cellular senescence Elderly patients MAFB-NOTCH3axis Methylmalonic acid Osteosarcoma PI3K-AKTpathway |
| title | Cellular senescence-driven transcriptional reprogramming of the MAFB/NOTCH3 axis activates the PI3K/AKT pathway and promotes osteosarcoma progression |
| title_full | Cellular senescence-driven transcriptional reprogramming of the MAFB/NOTCH3 axis activates the PI3K/AKT pathway and promotes osteosarcoma progression |
| title_fullStr | Cellular senescence-driven transcriptional reprogramming of the MAFB/NOTCH3 axis activates the PI3K/AKT pathway and promotes osteosarcoma progression |
| title_full_unstemmed | Cellular senescence-driven transcriptional reprogramming of the MAFB/NOTCH3 axis activates the PI3K/AKT pathway and promotes osteosarcoma progression |
| title_short | Cellular senescence-driven transcriptional reprogramming of the MAFB/NOTCH3 axis activates the PI3K/AKT pathway and promotes osteosarcoma progression |
| title_sort | cellular senescence driven transcriptional reprogramming of the mafb notch3 axis activates the pi3k akt pathway and promotes osteosarcoma progression |
| topic | Cellular senescence Elderly patients MAFB-NOTCH3axis Methylmalonic acid Osteosarcoma PI3K-AKTpathway |
| url | http://www.sciencedirect.com/science/article/pii/S2352304223000806 |
| work_keys_str_mv | AT zhenhaozhang cellularsenescencedriventranscriptionalreprogrammingofthemafbnotch3axisactivatesthepi3kaktpathwayandpromotesosteosarcomaprogression AT doudoujing cellularsenescencedriventranscriptionalreprogrammingofthemafbnotch3axisactivatesthepi3kaktpathwayandpromotesosteosarcomaprogression AT baijunxuan cellularsenescencedriventranscriptionalreprogrammingofthemafbnotch3axisactivatesthepi3kaktpathwayandpromotesosteosarcomaprogression AT zhicaizhang cellularsenescencedriventranscriptionalreprogrammingofthemafbnotch3axisactivatesthepi3kaktpathwayandpromotesosteosarcomaprogression AT weiwu cellularsenescencedriventranscriptionalreprogrammingofthemafbnotch3axisactivatesthepi3kaktpathwayandpromotesosteosarcomaprogression AT zengwushao cellularsenescencedriventranscriptionalreprogrammingofthemafbnotch3axisactivatesthepi3kaktpathwayandpromotesosteosarcomaprogression |