UPMC Hillman Cancer Center, Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
J Virol. 2019 Feb 5;93(4). doi: 10.1128/JVI.01599-18. Print 2019 Feb 15.
Cancer cells are required to rewire existing metabolic pathways to support their abnormal proliferation. We have previously shown that, unlike glucose-addicted cancers, Kaposi's sarcoma-associated herpesvirus (KSHV)-transformed cells depend on glutamine rather than glucose for energy production and amino acid and nucleotide syntheses. High-level consumption of glutamine is tightly regulated and often coupled with the citrulline-nitric oxide (NO) cycle. We have found that KSHV infection accelerates nitrogen efflux by upregulating the expression of argininosuccinate synthase 1 (ASS1), a key enzyme in the citrulline-NO cycle. KSHV utilizes multiple microRNAs to upregulate expression. Depletion of either ASS1 or inducible nitric oxide synthase (iNOS) in KSHV-transformed cells suppresses growth proliferation, abolishes colony formation in soft agar, and decreases NO generation. Furthermore, by maintaining intracellular NO levels, expression facilitates KSHV-mediated activation of the STAT3 pathway, which is critical for virus-induced transformation. These results illustrate a novel mechanism by which an oncogenic virus hijacks a key metabolic pathway to promote growth transformation and reveal a potential novel therapeutic target for KSHV-induced malignancies. We have previously shown that Kaposi's sarcoma-associated herpesvirus (KSHV)-transformed cells depend on glutamine rather than glucose for energy production and amino acid and nucleotide syntheses. In this study, we have further examined how the KSHV-reprogramed metabolic pathways are regulated and discovered that KSHV hijacks the citrulline-nitric oxide (NO) cycle to promote growth proliferation and transformation. Multiple KSHV-encoded microRNAs upregulate argininosuccinate synthase 1 (ASS1), a key enzyme in the citrulline-NO cycle. is required for KSHV-induced proliferation, colony formation in soft agar, and NO generation of KSHV-transformed cells, which also depends on inducible nitric oxide synthase. By maintaining intracellular NO levels, mediates KSHV activation of the STAT3 pathway, which is essential for KSHV-induced abnormal cell proliferation and transformation. These results illustrate a novel mechanism by which an oncogenic virus hijacks a key metabolic pathway to promote growth transformation and reveal a potential novel therapeutic target for KSHV-induced malignancies.
癌细胞需要重新布线现有的代谢途径，以支持其异常增殖。我们之前已经表明，与葡萄糖成瘾性癌症不同，卡波济肉瘤相关疱疹病毒（KSHV）转化的细胞依赖于谷氨酰胺而不是葡萄糖来产生能量和合成氨基酸和核苷酸。谷氨酰胺的高水平消耗受到严格调节，并且通常与瓜氨酸-一氧化氮（NO）循环偶联。我们发现，KSHV 感染通过上调精氨酸琥珀酸合成酶 1（ASS1）的表达来加速氮的流出，ASS1 是瓜氨酸-NO 循环中的关键酶。KSHV 利用多种 microRNAs 上调表达。在 KSHV 转化的细胞中耗尽 ASS1 或诱导型一氧化氮合酶（iNOS）可抑制生长增殖，消除软琼脂中的集落形成，并减少 NO 的产生。此外，通过维持细胞内 NO 水平，促进 KSHV 介导的 STAT3 途径的激活，这对于病毒诱导的转化至关重要。这些结果说明了一种新的机制，即致癌病毒劫持关键代谢途径以促进生长转化，并揭示了 KSHV 诱导的恶性肿瘤的潜在新治疗靶点。我们之前已经表明，卡波济肉瘤相关疱疹病毒（KSHV）转化的细胞依赖于谷氨酰胺而不是葡萄糖来产生能量和合成氨基酸和核苷酸。在这项研究中，我们进一步研究了 KSHV 重新编程的代谢途径是如何被调节的，并发现 KSHV 劫持瓜氨酸-NO（NO）循环来促进生长增殖和转化。多种 KSHV 编码的 microRNAs 上调精氨酸琥珀酸合成酶 1（ASS1），ASS1 是瓜氨酸-NO 循环中的关键酶。在 KSHV 诱导的增殖、软琼脂中的集落形成和 KSHV 转化细胞的 NO 产生中，需要，这也依赖于诱导型一氧化氮合酶。通过维持细胞内 NO 水平，介导 KSHV 激活 STAT3 途径，该途径对于 KSHV 诱导的异常细胞增殖和转化至关重要。这些结果说明了一种新的机制，即致癌病毒劫持关键代谢途径以促进生长转化，并揭示了 KSHV 诱导的恶性肿瘤的潜在新治疗靶点。
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