한빛사 논문
Un Yung Choia, Jae Jin Leea, Angela Parka, Wei Zhub, Hye-Ra Leec, Youn Jung Choia, Ji-Seung Yood, Claire Yub, Pinghui Fenga,e, Shou-Jiang Gaoa,f,g, Shaochen Chenb, Hyungjin Eoha,1, and Jae U. Junga,1
aDepartment of Molecular Microbiologyand Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033; bDepartment of NanoEngineering, University of California San Diego, La Jolla, CA 92093; cDepartment of Biotechnology and Bioinformatics, College of Science and Technology, Korea University, 30019 Sejong, South Korea; dDepartment of Immunology, Faculty of Medicine, Hokkaido University, 060-8638 Sapporo, Japan; eSection of Infection and Immunity, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90089; fUniversity of Pittsburgh Medical Center (UPMC), Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15219; and gLaboratory of Human Virology and Oncology, Shantou University Medical College, 515041 Shantou, Guangdong, China
1To whom correspondence may be addressed.
Abstract
Three-dimensional (3D) cell culture is well documented to regain intrinsic metabolic properties and to better mimic the in vivo situation than two-dimensional (2D) cell culture. Particularly, proline metabolism is critical for tumorigenesis since pyrroline-5-carboxylate (P5C) reductase (PYCR/P5CR) is highly expressed in various tumors and its enzymatic activity is essential for in vitro 3D tumor cell growth and in vivo tumorigenesis. PYCR converts the P5C intermediate to proline as a biosynthesis pathway, whereas proline dehydrogenase (PRODH) breaks down proline to P5C as a degradation pathway. Intriguingly, expressions of proline biosynthesis PYCR gene and proline degradation PRODH gene are up-regulated directly by c-Myc oncoprotein and p53 tumor suppressor, respectively, suggesting that the proline-P5C metabolic axis is a key checkpoint for tumor cell growth. Here, we report a metabolic reprogramming of 3D tumor cell growth by oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV), an etiological agent of Kaposi’s sarcoma and primary effusion lymphoma. Metabolomic analyses revealed that KSHV infection increased nonessential amino acid metabolites, specifically proline, in 3D culture, not in 2D culture. Strikingly, the KSHV K1 oncoprotein interacted with and activated PYCR enzyme, increasing intracellular proline concentration. Consequently, the K1-PYCR interaction promoted tumor cell growth in 3D spheroid culture and tumorigenesis in nude mice. In contrast, depletion of PYCR expression markedly abrogated K1-induced tumor cell growth in 3D culture, not in 2D culture. This study demonstrates that an increase of proline biosynthesis induced by K1-PYCR interaction is critical for KSHV-mediated transformation in in vitro 3D culture condition and in vivo tumorigenesis.
cancer metabolism, proline metabolism, pyrroline-5-carboxylate reductase (PYCR), Kaposi's sarcoma-associated herpesvirus (KSHV), K1
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