Department of Medicine II, Molecular Hepatology Section, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
Department of Medicine II, Molecular Hepatology Section, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
EBioMedicine. 2020 Apr;54:102699. doi: 10.1016/j.ebiom.2020.102699. Epub 2020 Apr 21.
The extracellular signal-regulated kinase (ERK) pathway regulates cell growth, and is hyper-activated and associated with drug resistance in hepatocellular carcinoma (HCC). Metabolic pathways are profoundly dysregulated in HCC. Whether an altered metabolic state is linked to activated ERK pathway and drug response in HCC is unaddressed.
We deprived HCC cells of glutamine to induce metabolic alterations and performed various assays, including metabolomics (with C-glucose isotope tracing), microarray analysis, and cell proliferation assays. Glutamine-deprived cells were also treated with kinase inhibitors (e.g. Sorafenib, Erlotinib, U0126 amongst other MEK inhibitors). We performed bioinformatics analysis and stratification of HCC tumour microarrays to determine upregulated ERK gene signatures in patients.
In a subset of HCC cells, the withdrawal of glutamine triggers a severe metabolic alteration and ERK phosphorylation (pERK). This is accompanied by resistance to the anti-proliferative effect of kinase inhibitors, despite pERK inhibition. High intracellular serine is a consistent feature of an altered metabolic state and contributes to pERK induction and the kinase inhibitor resistance. Blocking the ERK pathway facilitates cell proliferation by reprogramming metabolism, notably enhancing aerobic glycolysis. We have identified 24 highly expressed ERK gene signatures that their combined expression strongly indicates a dysregulated metabolic gene network in human HCC tissues.
A severely compromised metabolism lead to ERK pathway induction, and primes some HCC cells to pro-survival phenotypes upon ERK pathway blockade. Our findings offer novel insights for understanding, predicting and overcoming drug resistance in liver cancer patients. FUND: DFG, BMBF and Sino-German Cooperation Project.
细胞外信号调节激酶（ERK）通路调节细胞生长，在肝癌（HCC）中被过度激活并与耐药性相关。肝癌中代谢途径严重失调。代谢状态的改变是否与 HCC 中激活的 ERK 通路和药物反应有关尚不清楚。
我们剥夺 HCC 细胞的谷氨酰胺以诱导代谢改变，并进行了各种测定，包括代谢组学（使用 C-葡萄糖同位素示踪）、微阵列分析和细胞增殖测定。还用激酶抑制剂（如 Sorafenib、Erlotinib、U0126 等 MEK 抑制剂）处理谷氨酰胺剥夺的细胞。我们进行了生物信息学分析和 HCC 肿瘤微阵列的分层，以确定患者中上调的 ERK 基因特征。
在 HCC 细胞的一部分中，谷氨酰胺的去除会引发严重的代谢改变和 ERK 磷酸化（pERK）。这伴随着对激酶抑制剂的抗增殖作用的抵抗，尽管 pERK 抑制。高细胞内丝氨酸是代谢改变的一致特征，有助于 pERK 诱导和激酶抑制剂耐药性。阻断 ERK 通路通过重新编程代谢来促进细胞增殖，特别是增强有氧糖酵解。我们已经确定了 24 个高表达的 ERK 基因特征，它们的组合表达强烈表明在人类 HCC 组织中存在失调的代谢基因网络。
严重受损的代谢导致 ERK 通路的诱导，并使一些 HCC 细胞在 ERK 通路阻断时呈现出抗生存表型。我们的发现为理解、预测和克服肝癌患者的耐药性提供了新的见解。
DFG、BMBF 和中德合作项目。
