Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar (Mohali), Punjab, India.
J Biochem Mol Toxicol. 2024 Mar;38(3):e23663. doi: 10.1002/jbt.23663.
Hepatocellular carcinoma (HCC) is the third most common cancer-related cause of death worldwide. Although Sorafenib is the standard systemic therapy for treating HCC, but it develops resistance very quickly, leading to poor prognosis. The current study was planned to explore the effect of l-methionine on the anticancer activity of Sorafenib in HCC. Ten millimolar of l-methionine treatment significantly reduced the IC of Sorafenib from 5.513 ± 0.171 to 0.8095 ± 0.0465 µM in HepG2 cell line. It also resulted in concomitant increase in oxidative stress and deactivation of ERK/AMPK/AKT pathway. Additionally, it also resulted in the increased expression of dual specificity phosphatase 3 (DUSP3). In a rat model of sorafenib-resistant HCC induced by diethylnitrosamine (DEN) (100 mg/L/day) and Sorafenib (10 mg/kg), l-methionine (300 and 500 mg/kg/day) supplementation overcame the drug resistance, as indicated by the reduced formation of surface tumor nodules, prevention of cellular hypertrophy, hyperplasia and inflammation, and improved animal survival. Furthermore, l-methionine in combination with Sorafenib also inhibited AMPK/AKT and ERK pathway. At chromatin level, l-methionine supplementation prevented global methylation of H3K27me3, an inactivation mark, and demethylation of H3K36me2, an activation mark. Interestingly, our findings suggest that inhibition of the ERK pathway via increased activity of DUSP3 is epigenetically regulated. Besides, chromatin immunoprecipitation data exhibited augmented H3K36me2 (an activation mark) levels on the DUSP3 promoter region. To the best of our knowledge, we are the first to report that l-methionine supplementation improves the chemosensitivity in Sorafenib-resistant HCC via modulating the epigenetic landscape and can be a potential therapeutic strategy.
肝细胞癌（HCC）是全球第三大常见的癌症相关死亡原因。索拉非尼虽然是治疗 HCC 的标准系统治疗方法，但它很快就会产生耐药性，导致预后不良。本研究旨在探讨 L-蛋氨酸对 HCC 中索拉非尼抗癌活性的影响。10 毫摩尔 L-蛋氨酸处理将索拉非尼的 IC 在 HepG2 细胞系中从 5.513±0.171 降低至 0.8095±0.0465 µM。它还导致氧化应激增加和 ERK/AMPK/AKT 通路失活。此外，它还导致双特异性磷酸酶 3（DUSP3）的表达增加。在用二乙基亚硝胺（DEN）（100mg/L/天）和索拉非尼（10mg/kg）诱导的索拉非尼耐药 HCC 大鼠模型中，L-蛋氨酸（300 和 500mg/kg/天）补充克服了耐药性，表现为表面肿瘤结节形成减少，细胞肥大、增生和炎症得到预防，动物存活率提高。此外，L-蛋氨酸与索拉非尼联合使用也抑制了 AMPK/AKT 和 ERK 通路。在染色质水平上，L-蛋氨酸补充阻止了 H3K27me3 的全局甲基化，H3K27me3 是一种失活标记，以及 H3K36me2 的去甲基化，H3K36me2 是一种激活标记。有趣的是，我们的研究结果表明，ERK 通路的抑制是通过 DUSP3 活性的增加而受到表观遗传调控的。此外，染色质免疫沉淀数据显示，DUSP3 启动子区域的 H3K36me2（激活标记）水平增加。据我们所知，我们是第一个报道 L-蛋氨酸补充通过调节表观遗传景观提高索拉非尼耐药 HCC 的化疗敏感性，并可能成为一种潜在的治疗策略。
