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首页> 外文期刊>Molecular Cancer >TNFα and IL-17 cooperatively stimulate glucose metabolism and growth factor production in human colorectal cancer cells
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TNFα and IL-17 cooperatively stimulate glucose metabolism and growth factor production in human colorectal cancer cells

机译：TNFα和IL-17协同刺激人大肠癌细胞的葡萄糖代谢和生长因子的产生

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Background Inflammation is a well-known etiological factor for colorectal cancer, but mechanisms underlying the linkage between inflammation and cancer are incompletely understood. We hypothesized that two pro-inflammatory cytokines, TNFα and IL-17, might play a role in promoting colorectal carcinogenesis. Aerobic glycolysis is a metabolic adaptation that promotes the survival/proliferation of cancer cells. Paracrine signaling between tumor cells and cancer-associated fibroblasts also plays a role in carcinogenesis. Methods The effect of TNFα and IL-17 on aerobic glycolysis and growth factor production in cultured human colorectal cancer cells was investigated. Glucose utilization and lactate production were quantified by measuring the disappearance of glucose and appearance of lactate in the culture medium. Glucose transporter and glycolytic enzyme expression levels were measured by immunoblotting. Results TNFα and IL-17 cooperatively stimulated glycolysis in HT-29, T84, Caco-2 and HCT116 colorectal cancer cells. Treatment of HT-29 cells with TNFα plus IL-17 also increased the expression of HIF-1α and c-myc, two factors know to induce the transcription of genes encoding components of the glycolytic pathway. To further investigate mechanisms for cytokine-stimulated glycolysis, the effects of TNFα and IL-17 on expression of six members and one regulator of the glycolytic pathway were investigated. TNFα and IL-17 cooperatively increased the expression of the glucose transporter SLC2A1 and hexokinase-2 but did not regulate expression of glucose transporter SLC2A3, enolase-1, pyruvate kinase M2, lactate dehydrogenase A, or 6-phoshofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3). Experiments with inhibitors indicated that HIF-1α played a role in induction of SLC2A1 and that the transcription factor NF-κB played a role in induction of hexokinase-2 by TNFα and IL-17. TNFα and IL-17 also synergistically stimulated production by HT-29 cells of a growth factor that simulated proliferation/survival of NIL8 fibroblastic cells. The activity of this factor was not specifically inhibited by the EGFR inhibitor AG1478, indicating that it is not an EGFR ligand. Conclusions Chronic inflammation is known to promote colorectal tumorigenesis. The pro-inflammatory cytokines TNFα and IL-17 may contribute to this effect by stimulating glycolysis and growth factor production in colorectal cancer cells.
机译：背景炎症是大肠癌的众所周知的病因，但对炎症和癌症之间联系的潜在机制尚不完全了解。我们假设两种促炎细胞因子TNFα和IL-17可能在促进结直肠癌发生中起作用。有氧糖酵解是一种新陈代谢适应机制，可促进癌细胞的存活/增殖。肿瘤细胞与癌症相关的成纤维细胞之间的旁分泌信号传导也在致癌作用中起作用。方法研究TNFα和IL-17对人大肠癌细胞有氧糖酵解和生长因子产生的影响。通过测量培养基中葡萄糖的消失和乳酸的出现来定量葡萄糖的利用和乳酸的产生。通过免疫印迹测量葡萄糖转运蛋白和糖酵解酶的表达水平。结果TNFα和IL-17在HT-29，T84，Caco-2和HCT116结直肠癌细胞中协同刺激糖酵解。用TNFα加IL-17处理HT-29细胞也增加了HIF-1α和c-myc的表达，这是两个已知诱导糖酵解途径成分基因转录的因子。为了进一步研究细胞因子刺激的糖酵解的机制，研究了TNFα和IL-17对糖酵解途径的六种成员和一种调节剂的表达的影响。 TNFα和IL-17协同增加葡萄糖转运蛋白SLC2A1和己糖激酶2的表达，但不调节葡萄糖转运蛋白SLC2A3，烯醇酶1，丙酮酸激酶M2，乳酸脱氢酶A或6磷酸果糖-2-激酶/果糖的表达。 -2,6-双磷酸酶-3（PFKFB3）。抑制剂实验表明，HIF-1α在诱导SLC2A1中起作用，转录因子NF-κB在TNFα和IL-17诱导己糖激酶-2中起作用。 TNFα和IL-17还协同刺激HT-29细胞产生模拟NIL8成纤维细胞增殖/存活的生长因子。 EGFR抑制剂AG1478没有特异性抑制该因子的活性，表明它不是EGFR配体。结论已知慢性炎症可促进结直肠肿瘤发生。促炎细胞因子TNFα和IL-17可通过刺激结肠直肠癌细胞中的糖酵解和生长因子产生来促进这种作用。

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