Yu Xiang1, Bin Fang2, Yilin Liu3, Siqi Yan3, Dedong Cao4, Huiling Mei5, Qiuguo Wang6, Yu Hu7, Tao Guo8. 1. Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, Wuhan 430022, China. 2. Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. 3. Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. 4. Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060, China. 5. Department of Rheumatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. 6. Pediatrics Department of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. 7. Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: dr_huyu@126.com. 8. Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: guotao1968@163.com.
Abstract
AIMS: Multiple myeloma (MM) was recently reported to rely on increased oxidative phosphorylation (OXPHOS) for survival, providing a potential opportunity for MM therapy. Herein, we aimed to propose a novel targeted drug for MM treatment, followed by the exploration of reason for OXPHOS enhancement in MM cells. MATERIALS AND METHODS: The expression of OXPHOS genes and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) was analyzed using bioinformatics analyses, followed by verification in MM cell lines. The effects of SR18292 on OXPHOS were measured by qRT-PCR, Western blot, transmission electron microscopy, oxygen consumption rate and so on. The proliferation and apoptosis were evaluated by CCK-8, flow cytometry and Western blot. The efficiency and safety of SR18292 were assessed in a mouse model of MM. KEY FINDINGS: The OXPHOS genes were generally overexpressed in MM cells, which was associated with poorer prognosis of MM patients. PGC-1α, a transcriptional coactivator, was upregulated in MM cells, and MM patients with higher PGC-1α expression exhibited increased enrichment of the OXPHOS gene set. Treatment with SR18292 (an inhibitor of PGC-1α) significantly impaired the proliferation and survival of MM cells due to OXPHOS metabolism dysfunction, which leads to energy exhaustion and oxidative damage. Besides, SR18292 potently inhibited tumor growth at a well-tolerated dose in MM model mice. SIGNIFICANCE: The overexpression of OXPHOS gene set mediated by upregulated PGC-1α provides a structural basis for enhanced OXPHOS in MM cells, and SR18292 (a PGC-1α inhibitor) exerts potent antimyeloma effects, offering a potential tangible avenue for MM therapy.
AIMS: Multiple myeloma (MM) was recently reported to rely on increased oxidative phosphorylation (OXPHOS) for survival, providing a potential opportunity for MM therapy. Herein, we aimed to propose a novel targeted drug for MM treatment, followed by the exploration of reason for OXPHOS enhancement in MM cells. MATERIALS AND METHODS: The expression of OXPHOS genes and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) was analyzed using bioinformatics analyses, followed by verification in MM cell lines. The effects of SR18292 on OXPHOS were measured by qRT-PCR, Western blot, transmission electron microscopy, oxygen consumption rate and so on. The proliferation and apoptosis were evaluated by CCK-8, flow cytometry and Western blot. The efficiency and safety of SR18292 were assessed in a mouse model of MM. KEY FINDINGS: The OXPHOS genes were generally overexpressed in MM cells, which was associated with poorer prognosis of MM patients. PGC-1α, a transcriptional coactivator, was upregulated in MM cells, and MM patients with higher PGC-1α expression exhibited increased enrichment of the OXPHOS gene set. Treatment with SR18292 (an inhibitor of PGC-1α) significantly impaired the proliferation and survival of MM cells due to OXPHOS metabolism dysfunction, which leads to energy exhaustion and oxidative damage. Besides, SR18292 potently inhibited tumor growth at a well-tolerated dose in MM model mice. SIGNIFICANCE: The overexpression of OXPHOS gene set mediated by upregulated PGC-1α provides a structural basis for enhanced OXPHOS in MM cells, and SR18292 (a PGC-1α inhibitor) exerts potent antimyeloma effects, offering a potential tangible avenue for MM therapy.
Authors: Birgit Knoechel; Jens G Lohr; Johannes M Waldschmidt; Jake A Kloeber; Praveen Anand; Julia Frede; Antonis Kokkalis; Valeriya Dimitrova; Sayalee Potdar; Monica S Nair; Tushara Vijaykumar; Nam Gyu Im; Amy Guillaumet-Adkins; Nitish Chopra; Hannah Stuart; Lillian Budano; Noori Sotudeh; Guangwu Guo; Clemens Grassberger; Andrew J Yee; Jacob P Laubach; Paul G Richardson; Kenneth C Anderson; Noopur S Raje Journal: Clin Cancer Res Date: 2021-09-13 Impact factor: 13.801