Department of Pharmacy, The Affiliated Hospital of Ningbo University Medical School, Ningbo, P. R. China.
School of Medicine, Ningbo University, Ningbo, P. R. China.
Life Sci Alliance. 2023 Jan 20;6(3). doi: 10.26508/lsa.202201660. Print 2023 Mar.
For the past decade, the prevalence and mortality of methamphetamine (METH) use have doubled, suggesting that METH use could be the next substance use crisis worldwide. Ingested METH is transformed into other products in the liver, a major metabolic organ. Studies have revealed that METH causes deleterious inflammatory response, oxidative stress, and extensive DNA damage. These pathological damages are driving factors of hepatocellular carcinoma (HCC). Nonetheless, the potential role of METH in HCC and the underlying mechanisms remain unknown. Herein, we found a higher HCC incidence in METH abusers. METH promoted cellular proliferation, migration, and invasion in two human-derived HCC cells. Consistently, METH uptake promoted HCC progression in a xenograft mouse model. Mechanistically, METH exposure induced ROS production, which activated the Ras/MEK/ERK signaling pathway. Clearance of ROS by NAC suppressed METH-induced activation of Ras/ERK1/2 pathways, leading to arrest of HCC xenograft formation in nude mice. To the best of our knowledge, this is the first study to substantiate that METH promotes HCC progression and inhibition of ROS may reverse this process.
在过去的十年中，冰毒（METH）的使用率和死亡率翻了一番，这表明 METH 使用可能成为全球下一个药物使用危机。摄入的 METH 在肝脏（主要代谢器官）中转化为其他物质。研究表明，METH 会引起有害的炎症反应、氧化应激和广泛的 DNA 损伤。这些病理损伤是肝细胞癌（HCC）的驱动因素。尽管如此，METH 在 HCC 中的潜在作用及其潜在机制仍不清楚。在此，我们发现 METH 滥用者的 HCC 发病率更高。METH 促进了两种人源性 HCC 细胞的细胞增殖、迁移和侵袭。一致地，METH 摄取促进了异种移植小鼠模型中的 HCC 进展。在机制上，METH 暴露会诱导 ROS 产生，从而激活 Ras/MEK/ERK 信号通路。通过 NAC 清除 ROS 可以抑制 METH 诱导的 Ras/ERK1/2 通路的激活，从而导致裸鼠中 HCC 异种移植物的形成受阻。据我们所知，这是第一项证实 METH 促进 HCC 进展的研究，而抑制 ROS 可能会逆转这一过程。
