Pharmacological or genetic inhibition of LDHA reverses tumor progression of pediatric osteosarcoma.
Reprogrammed energy metabolism is an emerging hallmark of cancer. Lactate dehydrogenase A (LDHA), a key enzyme involved in anaerobic glycolysis, is frequently deregulated in human malignancies. However, limited knowledge is known about its roles in the progression of osteosarcoma (OS). In this study, we found that LDHA is commonly upregulated in four OS cell lines compared with the normal osteoblast cells (hFOB1.19). Treatment with FX11, a specific inhibitor of LDHA, significantly reduced LDHA activity, and inhibited cell proliferation and invasive potential in a dose dependent manner. Genetic silencing of LDHA resulted in a decreased lactate level in the culture medium, reduced cell viability and decreased cell invasion ability. Meanwhile, silencing of LDHA also compromised tumorigenesis in vivo. Furthermore, knockdown of LDHA remarkably reduced extracellular acidification rate (ECAR) as well as glucose consumption. In the presence of 2-DG, a glycolysis inhibitor, LDHA-mediated cell proliferation and invasion were completely blocked, indicating the oncogenic activities of LDHA may dependent on Warburg effect. Finally, pharmacological inhibition of c-Myc or HIF1α significantly attenuated LDHA expression. Taken together, upregulated LDHA facilitates tumor progression of OS and might be a potential target for OS treatment.
Department of Pediatrics, Woman and Child Hospital of Hubei Province, Wuhan 430070, PR China.
Shan
S
Gao
Department of Pediatrics, Woman and Child Hospital of Hubei Province, Wuhan 430070, PR China.
Dan-Na
DN
Tu
Department of Pediatrics, Woman and Child Hospital of Hubei Province, Wuhan 430070, PR China.
Heng
H
Li
Department of Biliary-Hepatic Surgery, Affiliated Hospital of Guiyang Medical College, Guiyang 550001, PR China.
Jian-Xin
JX
Jiang
Department of Pediatrics, Woman and Child Hospital of Hubei Province, Wuhan 430070, PR China.
Xin
X
Cao
Department of Pediatrics, Woman and Child Hospital of Hubei Province, Wuhan 430070, PR China. Electronic address: Youjb5813@163.com.
Jin-Bin
JB
You
Department of Pediatrics, Woman and Child Hospital of Hubei Province, Wuhan 430070, PR China. Electronic address: 62724838@163.com.
Xiao-Qin
XQ
Zhou
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D018450:Disease Progression; D020868:Gene Silencing / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics*; D000080864:Lactate Dehydrogenase 5; D009281:Naphthalenes / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D012516:Osteosarcoma / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology
C547455:3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxylic acid; D007527:Isoenzymes; D009281:Naphthalenes; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5
Cell invasion; Cell proliferation; ECAR; LDHA; Osteosarcoma; Warburg effect