Lactate dehydrogenase inhibitors can reverse inflammation induced changes in colon cancer cells

乳酸脱氢酶 糖酵解 炎症 癌细胞 乳酸脱氢酶A 肿瘤微环境 厌氧糖酵解 癌症 癌症研究 基质金属蛋白酶 瓦博格效应 化学 生物 生物化学 新陈代谢 免疫学 内科学 医学 肿瘤细胞
作者
Marcella Manerba,Lorenza Di Ianni,Marzia Govoni,Marinella Roberti,Maurizio Recanatini,Giuseppina Di Stefano
出处
期刊:European Journal of Pharmaceutical Sciences [Elsevier BV]
卷期号:96: 37-44 被引量:55
标识
DOI:10.1016/j.ejps.2016.09.014
摘要

The inflammatory microenvironment is an essential component of neoplastic lesions and can significantly impact on tumor progression. Besides facilitating invasive growth, inflammatory cytokines were also found to reprogram cancer cell metabolism and to induce aerobic glycolysis. Previous studies did not consider the possible contribution played in these changes by lactate dehydrogenase (LDH). The A isoform of LDH (LDH-A) is the master regulator of aerobic glycolysis; it actively reduces pyruvate and causes enhanced lactate levels in tumor tissues. In cancer cells, lactate was recently found to directly increase migration ability; moreover, when released in the microenvironment, it can facilitate matrix remodeling. In this paper, we illustrate that treatment of human colon adenocarcinoma cells with TNF-α and IL-17, two pro-inflammatory cytokines, modifies LDH activity, causing a shift toward the A isoform which results in increased lactate production. At the same time, the two cytokines appeared to induce features of epithelial-mesenchymal transition in the treated cells, such as reduction of E-cadherin levels and increased secretion of metalloproteinases. Noteworthy, oxamate and galloflavin, two inhibitors of LDH activity which reduce lactate production in cells, were found to relieve the inflammation-induced effects. These results suggest LDH-A and/or lactate as common elements at the cross-road between cancer cell metabolism, tumor progression and inflammation. At present, LDH inhibitors suitable for clinical use are actively searched as possible anti-proliferative agents; our data lead to hypothesize for these compounds a wider potential in anticancer treatment.
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