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

Abstract

Abstract. Glioblastoma multiforme (GBM) is a prevalent and aggressive disease, and the development of a novel therapy to better treat advanced GBM is urgently required. Lactate dehydrogenase A (LDHA), which functions as a key enzyme in transforming pyruvate into lactate, has attracted more attention in recent years due to its critical role in various types of advanced cancer. Previous data derived from the Oncomine database have shown that the expression of LDHA is higher in GBM tissues than that in corresponding normal control tissues. However, the association of LDHA levels with glioma clinical grades and the possible mechanisms of LDHA in GBM progression have not been investigated. The present study showed that there is a significant positive correlation between LDHA expression levels and tumor clinical stages. The knockdown of LDHA inhibited cell growth by inhibiting cell cycle progression and inducing apoptosis in glioma cell lines. Upon investigating the molecular mechanism, LDHA knockdown via siRNA treatment was associated with decreased cyclin D1 expression, increased cleavage of PARP, and altered B-cell lymphoma 2 and B-cell lymphoma 2-associated protein X expression. In addition, LDHA knockdown led to the marked downregulation of matrix metalloproteinase (MMP)-2, MMP-9, VE-Cadherin and vascular endothelial growth factor expression levels. Furthermore, knock down of LDHA enhanced the chemosensitivity of glioma cells to temozolomide (TMZ), a second-generation alkylating agent with activity against recurrent high-grade glioma. These findings support LDHA as a novel target for developing effective therapeutic strategies to treat GBM.

Targeting Glutamine Addiction in Gliomas

“…In different brain tumors, high lactate dehydrogenase (LDH) activity and an abnormal LDH isoform expression pattern was observed by Subhash et al [131], who analyzed 100 biopsy samples. Additionally, Di et al [132], investigating clinical samples, confirmed a positive correlation between LDHA expression and glioma grade. Moreover, silencing LDHA expression with siRNA in human GBM cell lines U87MG and U251MG resulted in growth inhibition and enhanced sensitivity to TMZ [132].…”

“…Additionally, Di et al [132], investigating clinical samples, confirmed a positive correlation between LDHA expression and glioma grade. Moreover, silencing LDHA expression with siRNA in human GBM cell lines U87MG and U251MG resulted in growth inhibition and enhanced sensitivity to TMZ [132]. Consistent results, confirming that LDHA upregulation results from a lack of cyclin G2-mediated inhibition of LDHA activity, were obtained by Li et al [133], who also employed the U87 and U251 plus mouse GL261 glioma cell lines.…”

Paclitaxel inhibits the migration of CD133⁺ U251 malignant glioma cells by reducing the expression of glycolytic enzymes

“…Additionally, an acidified microenvironment is likely to induce cell matrix degradation, microvessel formation and the Warburg effect (29). Moreover, silencing LDHA inhibited proliferation, induced apoptosis and increased the chemosensitivity of glioma cells to temozolomide (30). This indicates that PTX may effectively inhibit cancer cell growth and achieve its therapeutic effect by mediating the expression of glycolysis-related apoenzymes in GSCs.…”

The Positive Feedback Loop Between RLIP76 and HIF-1α Promotes Glycolysis and Tumorigenesis in Glioma Cells Under Hypoxic Conditions

“…It has been reported that HIF-1α is aberrantly expressed and inversely associated with prognosis in GBM patients [46]. Moreover, either suppressing HK2 activity by its inhibitor 3-bromopyruvate or downregulating LDHA by siRNA inhibits the malignant phenotype of glioma cells, suggesting that HIF-1α-responsive genes related to glycolysis could be potential targets for glioma treatment [47,48]. It has been well established that RLIP76 has a close association with several HIF-1αrelated genes, such as VEGFA and AKT, which leads to malignant development of gliomas [45,49].…”