Lactate dehydrogenase inhibitors can reverse inflammation induced changes in colon cancer cells.
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.
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Italy.
Marcella
M
Manerba
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Italy.
Lorenza
L
Di Ianni
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Italy.
Marzia
M
Govoni
Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Italy.
Marinella
M
Roberti
Department of Pharmacy and Biotechnology (FABIT), University of Bologna, Italy.
Maurizio
M
Recanatini
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Italy. Electronic address: giuseppina.distefano@unibo.it.
Giuseppina
G
Di Stefano
D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D020381:Interleukin-17 / Q000494:pharmacology; D049934:Isocoumarins / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D010072:Oxamic Acid / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D020381:Interleukin-17; D049934:Isocoumarins; D007527:Isoenzymes; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C572336:galloflavin; D019344:Lactic Acid; D007770:L-Lactate Dehydrogenase; D010072:Oxamic Acid
Cancer cell metabolism; Epithelial-mesenchymal transition; Inflammation; Lactate dehydrogenase