Purpose: Lactate dehydrogenase A (LDHA), which functions as a crucial enzyme in transforming from pyruvate into lactate, has been reported to be overexpressed in various advanced cancer and its silencing has turned out to be tumor suppressive. Previous studies have showed that the expression of LDHA was higher in renal cell carcinoma (RCC) than that in corresponding normal renal tissue. However, the function of LDHA in RCC, and its possible mechanism in tumor progression, has not been investigated. Methods: MTT and cell cycle assay were performed to explore the growth of the renal cells. Transwell assay for the migration and invasion and tube formation were conducted to detect the metastatic properties of the renal cancer. Results: Here, we show that siRNA-mediated knockdown of LDHA inhibits cell proliferation by decreasing cell cycle and promoting apoptosis in renal cancer cell lines. Mechanistically, LDHA siRNA treatment altered the expression of cell cycle- and apoptosis-related proteins, including p21, cyclin D1, Bcl-2 and Bax. In addition, LDHA siRNA treatment leads to markedly diminished migratory and invasive ability by reducing the expression of matrix metalloproteinase (MMP)-2 and MMP-9. Conclusions: These findings are consistent with the view that LDHA, as an oncogene, might be a potential therapeutic target in RCC.

Keywords:
Apoptosis, Invasion, Migration, Lactate dehydrogenase A, Renal cell carcinoma
1.
Ljungberg B, Campbell SC, Choi HY, Jacqmin D, Lee JE, Weikert S, Kiemeney LA: The epidemiology of renal cell carcinoma. Eur Urol 2011;60:615-621.
2.
Soltysova A, Breza J, Takacova M, Feruszova J, Hudecova S, Novotna B, Rozborilova E, Pastorekova S, Kadasi L, Krizanova O: Deregulation of energetic metabolism in the clear cell renal cell carcinoma: a multiple pathway analysis based on microarray profiling. Int J Oncol 2015;47:287-295.
3.
Ljungberg B, Bensalah K, Canfield S, Dabestani S, Hofmann F, Hora M, Kuczyk MA, Lam T, Marconi L, Merseburger AS, Mulders P, Powles T, Staehler M, Volpe A, Bex A: EAU guidelines on renal cell carcinoma: 2014 update. Eur Urol 2015;67:913-924.
4.
Ridge CA, Pua BB, Madoff DC: Epidemiology and staging of renal cell carcinoma. Semin Intervent Radiol 2014;31:3-8.
5.
Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J Clin 2013;63:11-30.
6.
Semenza GL: HIF-1 mediates the Warburg effect in clear cell renal carcinoma. J Bioenerg Biomembr 2007;39:231-234.
7.
Ljungberg B, Cowan NC, Hanbury DC, Hora M, Kuczyk MA, Merseburger AS, Patard JJ, Mulders PF, Sinescu IC: EAU guidelines on renal cell carcinoma: the 2010 update. Eur Urol 2010;58:398-406.
8.
Xu XD, Shao SX, Jiang HP, Cao YW, Wang YH, Yang XC, Wang YL, Wang XS, Niu HT: Warburg effect or reverse Warburg effect? A review of cancer metabolism. Oncol Res Treat 2015;38:117-122.
9.
Zong H, Zhang Y, You Y, Cai T, Wang Y: Decreased Warburg effect induced by ATP citrate lyase suppression inhibits tumor growth in pancreatic cancer. Med Oncol 2015;32:85.
10.
Zhang TB, Zhao Y, Tong ZX, Guan YF: Inhibition of glucose-transporter 1 (GLUT-1) expression reversed Warburg effect in gastric cancer cell MKN45. Int J Clin Exp Med 2015;8:2423-2428.
11.
Zhang S, Yang C, Yang Z, Zhang D, Ma X, Mills G, Liu Z: Homeostasis of redox status derived from glucose metabolic pathway could be the key to understanding the Warburg effect. Am J Cancer Res 2015;5:1265-1280.
12.
Wei H, Guo L, Li L, Zhou Q, Wu Z: [Mechanism of Warburg effect and its effect on tumor metastasis]. Zhongguo Fei Ai Za Zhi 2015;18:179-183.
13.
Chen Z, Lu W, Garcia-Prieto C, Huang P: The Warburg effect and its cancer therapeutic implications. J Bioenerg Biomembr 2007;39:267-274.
14.
Ooi AT, Gomperts BN: Molecular pathways: targeting cellular energy metabolism in cancer via inhibition of SLC2A1 and LDHA. Clin Cancer Res 2015;21:2440-2444.
15.
Xian ZY, Liu JM, Chen QK, Chen HZ, Ye CJ, Xue J, Yang HQ, Li JL, Liu XF, Kuang SJ: Inhibition of LDHA suppresses tumor progression in prostate cancer. Tumour Biol 2015;36:8093-8100.
16.
Qiu H, Jackson AL, Kilgore JE, Zhong Y, Chan LL, Gehrig PA, Zhou C, Bae-Jump VL: JQ1 suppresses tumor growth through downregulating LDHA in ovarian cancer. Oncotarget 2015;6:6915-6930.
17.
Lu QY, Zhang L, Yee JK, Go VW, Lee WN: Metabolic consequences of LDHA inhibition by epigallocatechin gallate and oxamate in MIA PaCa-2 pancreatic cancer cells. Metabolomics 2015;11:71-80.
18.
He TL, Zhang YJ, Jiang H, Li XH, Zhu H, Zheng KL: The c-Myc-LDHA axis positively regulates aerobic glycolysis and promotes tumor progression in pancreatic cancer. Med Oncol 2015;32:187.
19.
Wang ZY, Loo TY, Shen JG, Wang N, Wang DM, Yang DP, Mo SL, Guan XY, Chen JP: LDH-A silencing suppresses breast cancer tumorigenicity through induction of oxidative stress mediated mitochondrial pathway apoptosis. Breast Cancer Res Treat 2012;131:791-800.
20.
Girgis H, Masui O, White NM, Scorilas A, Rotondo F, Seivwright A, Gabril M, Filter ER, Girgis AH, Bjarnason GA, Jewett MA, Evans A, Al-Haddad S, Siu KM, Yousef GM: Lactate dehydrogenase A is a potential prognostic marker in clear cell renal cell carcinoma. Mol Cancer 2014;13:101.
21.
Singer K, Kastenberger M, Gottfried E, Hammerschmied CG, Büttner M, Aigner M, Seliger B, Walter B, Schlösser H, Hartmann A, Andreesen R, Mackensen A, Kreutz M: Warburg phenotype in renal cell carcinoma: high expression of glucose-transporter 1 (GLUT-1) correlates with low CD8(+) T-cell infiltration in the tumor. Int J Cancer 2011;128:2085-2095.
22.
Zhou L, Shen W, Niu DD, Tian KM, Prior BA, Shi GY, Singh S, Wang ZX: Fine tuning the transcription of ldhA for D-lactate production. J Ind Microbiol Biotechnol 2012;39:1209-1217.
23.
Elbaz M, Nasser MW, Ravi J, Wani NA, Ahirwar DK, Zhao H, Oghumu S, Satoskar AR, Shilo K, Carson WE 3rd, Ganju RK: Modulation of the tumor microenvironment and inhibition of EGF/EGFR pathway: novel anti-tumor mechanisms of cannabidiol in breast cancer. Mol Oncol 2015;9:906-919.
24.
Zheng Z, Ding M, Ni J, Song D, Huang J, Wang J: MiR-142 acts as a tumor suppressor in osteosarcoma cell lines by targeting Rac1. Oncol Rep 2015;33:1291-1299.
25.
Takahashi S: Vascular endothelial growth factor (VEGF), VEGF receptors and their inhibitors for antiangiogenic tumor therapy. Biol Pharm Bull 2011;34:1785-1788.
26.
Liu W, Xu J, Wang M, Wang Q, Bi Y, Han M: Tumor-derived vascular endothelial growth factor (VEGF) - a facilitates tumor metastasis through the VEGF-VEGFR1 signaling pathway. Int J Oncol 2011;39:1213-1220.
27.
Friedl J, Turner E, Alexander HR Jr: Augmentation of endothelial cell monolayer permeability by hyperthermia but not tumor necrosis factor: evidence for disruption of vascular integrity via VE-cadherin down-regulation. Int J Oncol 2003;23:611-616.
28.
Sandim V, Pereira DA, Ornellas AA, Alves G: Renal cell carcinoma and proteomics. Urol Int 2010;84:373-377.
29.
Can C, Acikalin MF, Ozen A, Dundar E: Prognostic impact of intratumoral C-reactive protein expression in patients with clear cell renal cell carcinoma. Urol Int 2014;92:270-275.
© 2016 S. Karger AG, Basel
2016
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.