PO.ET09.09 · 实验与分子治疗
靶向鸟氨酸氨基转移酶作为肝细胞癌的有前景治疗策略
Targeting ornithine aminotransferase as a promising therapeutic strategy for hepatocellular carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
肝细胞癌（HCC）占所有肝癌的90%，是全球癌症相关死亡的第二大原因。尽管经过数十年研究，其预后仍然不佳：每年约有800,000人被诊断为HCC，约80%在五年内死亡。在治疗方面，对更有效治疗手段存在关键的未满足需求。对当前一线多靶点酪氨酸激酶抑制剂sorafenib的耐药已日益普遍。此外，超过150项评估靶向药物、免疫疗法和联合方案的临床试验因疗效不足而失败，凸显了对新型、基于机制的治疗策略的迫切需求。新出现的证据强调了代谢重编程在包括HCC在内的多种癌症的致癌、治疗耐药和复发中的核心作用。鸟氨酸氨基转移酶（OAT）是这一过程中的关键酶，将氨基酸代谢（特别是谷氨酰胺和脯氨酸）与多胺生物合成及癌细胞增殖联系起来。OAT在HCC中过表达，并在临床前模型中被验证为治疗靶点。我们此前证明，OAT失活剂LHJ-2-79可有效抑制HepG2和Hep3B异种移植瘤的生长，并显著抑制Hep3B和HepG2细胞中甲胎蛋白（AFP，一种关键的HCC生物标志物）的分泌。然而，尚无OAT失活剂进入临床试验。为填补这一空白，我们实验室近期合成了新型OAT失活剂SS-1-148。在此，我们报告SS-1-148对HCC的影响，采用IC50分析、酶表达检测、异种移植生存研究、RNA-seq分析和代谢组学数据。我们的发现揭示了SS-1-148在效力、OAT活性抑制、肿瘤生长抑制、代谢基因表达以及脯氨酸和多胺水平改变方面存在细胞系依赖性差异。在体内，SS-1-148抑制Huh-7异种移植瘤生长，但对Huh-6肿瘤无效。对LHJ-2-79和SS-1-148在Huh-6和Huh-7细胞中的代谢组学分析进一步表明二者对脯氨酸和腐胺水平具有不同的影响，提示这两种失活剂具有不同的作用机制。总体而言，这些结果支持OAT作为HCC中有前景的治疗靶点，并为进一步开发基于OAT的治疗策略奠定基础。
查看英文原文 English abstract
Comprising 90% of all liver cancers, hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Despite decades of research, prognosis remains poor: approximately 800,000 people are diagnosed with HCC each year, and ~80% die within five years. Therapeutically, there is a critical unmet need for more effective treatments. Resistance to sorafenib, the current first-line multi-target tyrosine kinase inhibitor, has become increasingly common. Moreover, more than 150 clinical trials evaluating targeted agents, immunotherapies, and combination regimens have failed due to insufficient efficacy, underscoring the urgent need for novel, mechanism-based therapeutic strategies. Emerging evidence highlights the central role of metabolic reprogramming in carcinogenesis, treatment resistance, and recurrence across multiple cancers, including HCC. Ornithine aminotransferase (OAT) is a key enzyme in this process, linking amino acid metabolism, particularly glutamine and proline, to polyamine biosynthesis and cancer cell proliferation. OAT is overexpressed in HCC and validated as a therapeutic target in preclinical models. We previously demonstrated that the OAT inactivator LHJ-2-79 effectively inhibits tumor growth in HepG2 and Hep3B xenografts and significantly suppresses alpha-fetoprotein (AFP) secretion, a key HCC biomarker, in Hep3B and HepG2 cells. However, no OAT inactivators have yet advanced to clinical trials. To address this gap, our laboratory recently synthesized SS-1-148, a novel OAT inactivator. Here, we report the effects of SS-1-148 on HCC using IC50 profiling, enzyme expression assays, xenograft survival studies, RNA-seq analysis, and metabolomic data. Our findings reveal cell line-dependent differences in SS-1-148 potency, OAT activity inhibition, tumor growth suppression, metabolic gene expression, and alterations in proline and polyamine levels. In vivo, SS-1-148 inhibited Huh-7 xenograft growth but not Huh-6 tumors. Metabolomic analyses of LHJ-2-79 and SS-1-148 in Huh-6 and Huh-7 cells further demonstrated distinct effects on proline and putrescine levels, suggesting different mechanisms of action between the two inactivators. Collectively, these results support OAT as a promising therapeutic target in HCC and lay the foundation for further development of OAT-based treatment strategies.
利益披露 Disclosure
W. Qiang, None..
Y. Yang, None..
T. Ouyang, None..
V. Chen, None..
A. Qiu, None..
R. B. Silverman, None.