Oncogenic human herpesvirus hijacks proline metabolism for tumorigenesis.

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.

• Authors: Un Yung Choi, Jae Jin Lee, Angela Park, Wei Zhu, Hye-Ra Lee, Youn Jung Choi, Ji-Seung Yoo, Claire Yu, Pinghui Feng, Shou-Jiang Gao, Shaochen Chen, Hyungjin Eoh, Jae U Jung
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 14 Pg. 8083-8093 (04 07 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 32213586 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• K1 protein, Human herpesvirus 8
• Viral Proteins
• Proline
• Pyrroline Carboxylate Reductases
• delta-1-pyrroline-5-carboxylate reductase
• Proline Oxidase
• PRODH protein, human

Topics

• Animals
• Cell Culture Techniques (methods)
• Cell Line, Tumor
• Cell Proliferation
• Cell Transformation, Neoplastic (pathology)
• Herpesvirus 8, Human (metabolism)
• Humans
• Metabolomics
• Mice
• Proline (metabolism)
• Proline Oxidase (metabolism)
• Pyrroline Carboxylate Reductases (metabolism)
• Sarcoma, Kaposi (pathology, virology)
• Spheroids, Cellular
• Viral Proteins (metabolism)
• Xenograft Model Antitumor Assays