Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
Biomed Pharmacother. 2023 Oct;166:115293. doi: 10.1016/j.biopha.2023.115293. Epub 2023 Aug 9.
Hepatocellular carcinoma (HCC) is the most common primary malignant tumor. Although sorafenib and regorafenib have been approved for first-line and second-line treatment, respectively, of patients with advanced HCC, long-term treatment often results in acquired resistance. Given that glycolysis-mediated lactate production can contribute to drug resistance and impair HCC treatment efficacy, we investigated the effects of ketone body treatment on the metabolic shift in sorafenib-resistant HCC cells. We discovered differential expression of 3-hydroxymethyl glutaryl-CoA synthase 2 (HMGCS2) and the ketone body D-β-hydroxybutyrate (β-HB) in four sorafenib-resistant HCC cell lines. In sorafenib-resistant HCC cells, lower HMGCS2 and β-HB levels were correlated with more glycolytic alterations and higher lactate production. β-HB treatment enhanced pyruvate dehydrogenase (PDH) expression and decreased lactate dehydrogenase (LDHA) expression and lactate production in sorafenib-resistant HCC cells. Additionally, β-HB combined with sorafenib or regorafenib promoted the antiproliferative and antimigratory abilities of sorafenib-resistant HCC cells by inhibiting the B-raf/mitogen-activated protein kinase pathway and mesenchymal N-cadherin-vimentin axis. Although the in vivo β-HB administration did not affect tumor growth, the expression of proliferative and glycolytic proteins was inhibited in subcutaneous sorafenib-resistant tumors. In conclusion, exogenous β-HB treatment can reduce lactate production and reverse sorafenib resistance by inducing a glycolytic shift; it can also synergize with regorafenib for treating sorafenib-resistant HCC.
肝细胞癌（HCC）是最常见的原发性恶性肿瘤。尽管索拉非尼和瑞戈非尼分别被批准用于晚期 HCC 患者的一线和二线治疗，但长期治疗通常会导致获得性耐药。鉴于糖酵解介导的乳酸产生可能有助于耐药并损害 HCC 治疗效果，我们研究了酮体治疗对索拉非尼耐药 HCC 细胞代谢重排的影响。我们发现，在四种索拉非尼耐药 HCC 细胞系中，3-羟甲基戊二酰辅酶 A 合酶 2（HMGCS2）和酮体 D-β-羟基丁酸（β-HB）的表达存在差异。在索拉非尼耐药 HCC 细胞中，HMGCS2 和 β-HB 水平较低与更多的糖酵解改变和更高的乳酸产生相关。β-HB 处理增强了丙酮酸脱氢酶（PDH）的表达，并降低了乳酸脱氢酶（LDHA）的表达和乳酸的产生。此外，β-HB 与索拉非尼或瑞戈非尼联合使用通过抑制 B-raf/丝裂原活化蛋白激酶途径和间充质 N-钙黏蛋白-波形蛋白轴促进了索拉非尼耐药 HCC 细胞的增殖和迁移抑制能力。尽管体内β-HB 给药并不影响肿瘤生长，但索拉非尼耐药肿瘤的皮下表达的增殖和糖酵解蛋白受到抑制。总之，外源性β-HB 治疗通过诱导糖酵解重排可以减少乳酸的产生并逆转索拉非尼耐药性，还可以与瑞戈非尼协同治疗索拉非尼耐药性 HCC。
