Inhibition of LDHA Deliver Potential Anticancer Performance in Renal Cell Carcinoma

Abstract

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.

Silencing LDHA inhibits proliferation, induces apoptosis and increases chemosensitivity to temozolomide in glioma cells

“…LDHA catalyzes the conversion of pyruvate to lactate and is considered to be a key checkpoint of anaerobic glycolysis (9). Increased levels of LDHA have been reported in several types of tumors (11,(13)(14)(15), and its expression levels have been correlated with clinical stages in breast cancer, renal cell carcinoma and prostate cancer; these reports further support that therapies targeting LDHA may provide useful strategies for controlling cancer progression. Moreover, previous reports using data from the Oncomine database showed that the mRNA levels of LDHA were up-regulated in GBM compared to those in matched normal tissues; these results prompted us to determine the correlation between LDHA expression levels and glioma malignancy (16).…”

“…In pancreatic cancer, when LDHA was overexpressed, tumor growth was increased (13). In renal cell carcinoma, knocking down LDHA resulted in potential anticancer effects (14). Although the abnormal expression of LDHA has been reported in several cancers (10)(11)(12)(13)(14)(15), little is known about the expression pattern of LDHA and its underlying roles in GBM.…”

“…In renal cell carcinoma, knocking down LDHA resulted in potential anticancer effects (14). Although the abnormal expression of LDHA has been reported in several cancers (10)(11)(12)(13)(14)(15), little is known about the expression pattern of LDHA and its underlying roles in GBM. Previous reports using data from the Oncomine database showed that the mRNA levels of LDHA were up-regulated in GBM compared to matched tissues (16); these finding prompted us to examine the underlying role of LDHA in glioma malignancy.…”

“…The sequence of siRNA targeting LDHA (GenePharma, Shanghai, China) has been described previously: 5'-CGA ACT GGG CAG TAT AAAC-3'; negative control (NC), 5'-UUC UCC GAA CGU GUC ACG UTT-3' 14 . U87 and U251 cells were transfected with specific siRNAs using the Lipofectamine 2000 reagent in antibiotic-free Opti-MEM medium (both from Invitrogen; Thermo Fisher Scientific, Inc.) according to the manufacturer's protocol.…”

Stable shRNA Silencing of Lactate Dehydrogenase A (LDHA) in Human MDA-MB-231 Breast Cancer Cells Fails to Alter Lactic Acid Production, Glycolytic Activity, ATP or Survival

“…Experimental knockdown of LDHA in diverse malignant cell types has been reported to reduce glycolytic activity (5, 6), attenuate extruded lactate and ATP, tantamount to hampered cell proliferation, migration, invasion (7–10) and radio sensitization (11). Further, a number of studies are showing LDHA mRNA as being degraded by miRNAs: miR34a, miR-34c, miR-369-3p, miR-374a, and miR-4524a/b where overexpression of some of these can prevent resistance to radiation (8, 12) and chemotherapeutic drugs (13, 14).…”