Bladder cancer (BLCA) mortality is higher in African American (AA) patients compared with European American (EA) patients, but the molecular mechanism underlying race-specific differences are unknown. To address this gap, we conducted comprehensive RNA-Seq, proteomics, and metabolomics analysis of BLCA tumors from AA and EA. Our findings reveal a distinct metabolic phenotype in AA BLCA characterized by elevated mitochondrial oxidative phosphorylation (OXPHOS), particularly through the activation of complex I. The results provide insight into the complex I activation-driven higher OXPHOS activity resulting in glutamine-mediated metabolic rewiring and increased disease progression, which was also confirmed by [U]13C-glutamine tracing. Mechanistic studies further demonstrate that knockdown of NDUFB8, one of the components of complex I in AA BLCA cells, resulted in reduced basal respiration, ATP production, GLS1 expression, and proliferation. Moreover, preclinical studies demonstrate the therapeutic potential of targeting complex I, as evidenced by decreased tumor growth in NDUFB8-depleted AA BLCA tumors. Additionally, genetic and pharmacological inhibition of GLS1 attenuated mitochondrial respiration rates and tumor growth potential in AA BLCA. Taken together, these findings provide insight into BLCA disparity for targeting GLS1-Complex I for future therapy.
JCI insight. 2024 Sep 10*** epublish ***
Karthik Reddy Kami Reddy, Danthasinghe Waduge Badrajee Piyarathna, Jun Hyoung Park, Vasanta Putluri, Chandra Sekhar Amara, Abu Hena Mostafa Kamal, Jun Xu, Daniel Kraushaar, Shixia Huang, Sung Yun Jung, Livia S Eberlin, Jabril R Johnson, Rick A Kittles, Leomar Y Ballester, Krishna Parsawar, M Minhaj Siddiqui, Jianjun Gao, Adriana Langer Gramer, Roni J Bollag, Martha K Terris, Yair Lotan, Chad J Creighton, Seth P Lerner, Arun Sreekumar, Benny Abraham Kaipparettu, Nagireddy Putluri
Department of Molecular and Cellular Biology., Department of Molecular and Human Genetics., Dan L Duncan Comprehensive Cancer Center., Advanced Technology Cores., Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, and., Department of Surgery, Baylor College of Medicine, Houston, Texas, USA., Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, Georgia, USA., Department of Community Health and Preventive Medicine, Morehouse School of Medicine, Atlanta, Georgia, USA., Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Analytical and Biological Mass Spectrometry Core, University of Arizona, Tucson, Arizona, USA., Division of Urology, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Georgia Cancer Center, Augusta University, Augusta, Georgia, USA., Department of Urology, Medical College of Georgia, Augusta, Georgia, USA., Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
