Glucagon signaling via supraphysiologic GCGR can reduce cell viability without stimulating gluconeogenic gene expression in liver cancer cells.
Glucagon signaling via supraphysiologic GCGR can reduce cell viability without stimulating gluconeogenic gene expression in liver cancer cells.
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DOI：
10.1186/s40170-022-00280-1
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发表时间：
2022-02-05
影响因子：
5.9
通讯作者：
Simon MC
中科院分区：
文献类型：
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作者：
Godfrey J;Riscal R;Skuli N;Simon MC
葡萄糖代谢失调是癌症生长和生存的关键组成部分，通过 FDG-PET 成像显示肿瘤结节中葡萄糖摄取增强，临床上可以明显看出这一点。肿瘤细胞在各种相互关联的生化途径中利用葡萄糖来产生能量、合成代谢前体和生长所需的其他代谢物。胰高血糖素刺激的糖异生反对糖酵解，可能代表针对肿瘤细胞中葡萄糖代谢的途径特异性策略。在这里，我们测试了胰高血糖素信号传导是否可以激活糖异生以减少肝癌模型中的肿瘤增殖的假设。胰高血糖素受体 GCGR 在由一系列病因和遗传背景组成的肝癌细胞系中过度表达。通过 cAMP ELISA、磷酸化 PKA 底物的蛋白质印迹以及多种糖异生酶相对 mRNA 表达的 qPCR 来测量胰高血糖素信号转导。最后，进行细胞增殖和凋亡测定以量化胰高血糖素/GCGR刺激的生物学效应。用胰高血糖素处理的 SNU398 GCGR 细胞中的信号转导分析显示，cAMP 丰度增加，下游 PKA 底物（包括 CREB）磷酸化增加。 qPCR 数据表明，当用胰高血糖素处理时，SNU398 GCGR 细胞中的三个主要糖异生基因 G6PC、FBP1 或 PCK1 均未表现出显着较高的 mRNA 水平；然而，表观遗传抑制剂可能会部分增加这种情况。在胰高血糖素处理的 SNU398 GCGR 细胞中，细胞凋亡标记物的流式细胞术分析和生长测定可重复测量细胞活力的统计学显着降低。最后，采用 siCREB 抑制的增殖实验表明，用胰高血糖素处理的 SNU398 GCGR 细胞中的细胞死亡没有逆转，表明在此情况下胰高血糖素的作用与 CREB 无关。我们首次报道了胰高血糖素/GCGR 在肝癌中的潜在肿瘤抑制作用。具体来说，我们鉴定了一种新的细胞系特异性表型，其中胰高血糖素信号传导可以通过未确定的机制诱导细胞凋亡。未来的研究应该探讨胰高血糖素对糖尿病肝癌患者的潜在影响。在线版本包含可在 10.1186/s40170-022-00280-1 获取的补充材料。
Deregulated glucose metabolism is a critical component of cancer growth and survival, clinically evident via FDG-PET imaging of enhanced glucose uptake in tumor nodules. Tumor cells utilize glucose in a variety of interconnected biochemical pathways to generate energy, anabolic precursors, and other metabolites necessary for growth. Glucagon-stimulated gluconeogenesis opposes glycolysis, potentially representing a pathway-specific strategy for targeting glucose metabolism in tumor cells. Here, we test the hypothesis of whether glucagon signaling can activate gluconeogenesis to reduce tumor proliferation in models of liver cancer. The glucagon receptor, GCGR, was overexpressed in liver cancer cell lines consisting of a range of etiologies and genetic backgrounds. Glucagon signaling transduction was measured by cAMP ELISAs, western blots of phosphorylated PKA substrates, and qPCRs of relative mRNA expression of multiple gluconeogenic enzymes. Lastly, cell proliferation and apoptosis assays were performed to quantify the biological effect of glucagon/GCGR stimulation. Signaling analyses in SNU398 GCGR cells treated with glucagon revealed an increase in cAMP abundance and phosphorylation of downstream PKA substrates, including CREB. qPCR data indicated that none of the three major gluconeogenic genes, G6PC, FBP1, or PCK1, exhibit significantly higher mRNA levels in SNU398 GCGR cells when treated with glucagon; however, this could be partially increased with epigenetic inhibitors. In glucagon-treated SNU398 GCGR cells, flow cytometry analyses of apoptotic markers and growth assays reproducibly measured statistically significant reductions in cell viability. Finally, proliferation experiments employing siCREB inhibition showed no reversal of cell death in SNU398 GCGR cells treated with glucagon, indicating the effects of glucagon in this setting are independent of CREB. For the first time, we report a potential tumor suppressive role for glucagon/GCGR in liver cancer. Specifically, we identified a novel cell line-specific phenotype, whereby glucagon signaling can induce apoptosis via an undetermined mechanism. Future studies should explore the potential effects of glucagon in diabetic liver cancer patients. The online version contains supplementary material available at 10.1186/s40170-022-00280-1.
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DOI：
10.1158/1541-7786.mcr-14-0106-t
发表时间：
2014-11
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Abbadi S;Rodarte JJ;Abutaleb A;Lavell E;Smith CL;Ruff W;Schiller J;Olivi A;Levchenko A;Guerrero-Cazares H;Quinones-Hinojosa A
通讯作者：
Quinones-Hinojosa A
影响因子：
5.2
作者：
Lu, Chao;Ren, Chune;Yu, Zhenhai
通讯作者：
Yu, Zhenhai
影响因子：
11.2
作者：
Liao, Kun;Deng, Shuye;Li, Bo
通讯作者：
Li, Bo
影响因子：
3.7
作者：
Li J;Wang Y;Li QG;Xue JJ;Wang Z;Yuan X;Tong JD;Xu LC
通讯作者：
Xu LC
DOI：
10.1038/nrendo.2010.187
发表时间：
2010-12
期刊：
Nature reviews. Endocrinology
影响因子：
--
作者：
通讯作者：
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