Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance.

By V. Fantin, J. St-Pierre, P. Leder. Cancer Cell, 2006

1,658 citations recorded by the source corpus.

Alterations in cellular metabolism are among the most consistent hallmarks of cancer. Herein we have investigated the relationship between increased aerobic lactate production and mitochondrial physiology in tumor cells. To diminish the ability of malignant cells to metabolize pyruvate to lactate, lactate dehydrogenase A (LDH-A) levels were knocked down by means of LDH-A short hairpin RNAs. Reduction in LDH-A activity resulted in stimulation of mitochondrial respiration and decrease of mitochondrial membrane potential. It also compromised the ability of these tumor cells to proliferate under hypoxia. The tumorigenicity of the LDH-A-deficient cells was severely diminished, and this phenotype was reversed by complementation with the human ortholog LDH-A protein. These results demonstrate that LDH-A plays a key role in tumor maintenance.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/fc824bfe09130dab041c848e1caeeade733a3718

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Citations in the corpus

Hypoxia-Inducible Factor 1 and Dysregulated c-Myc Cooperatively Induce Vascular Endothelial Growth Factor and Metabolic Switches Hexokinase 2 and Pyruvate Dehydrogenase Kinase 1 (2007, background): “Because many cancer cells display the Warburg effect or have the propensity to take up glucose and convert glucose to lactate, rather than metabolizing glucose through oxidative phosphorylation (2, 7, 15, 19, 36, 76, 82, 83), we sought to understand how dysregulated expression of c-Myc might interac”
Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity (2010, result): “These results are consistent with previous studies that showed the inhibition of the glycolytic enzyme lactate dehydrogenase A (LDH-A) prevents anchorageindependent growth of Myc tumor cells and xenograft tumor formation of mouse mammary tumor cells by preventing the survival of these tumor cells un”
Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells. (2007, background): “In light of the most recent reports indicating that the tumor suppressor p53 gene regulates the balance between glycolysis and mitochondrial respiration (25), and LDH-A attenuation stimulates mitochondrial function (12), along with a rapidly growing body of evidence linking oncogenes and tumor suppr”
The LKB1-AMPK pathway: metabolism and growth control in tumor suppression (2009, background): “Indeed, this regulationof glucose metabolism by HIF1α contributes to tumorigenesis in multiple setting”
Blinded by the Light: The Growing Complexity of p53. (2009, background): “Indeed, the dependence of cancers on metabolic transformation is highlighted by mouse models of cancer in which interfering with these altered metabolic programs profoundly limits tumor cell growth (Bonnet et al., 2007; Christofk et al., 2008; Fantin et al., 2006).”
Understanding the intersections between metabolism and cancer biology (2017, positive): “Dependence on the enzyme lactate dehydrogenase (LDH) was demonstrated both genetically and pharmacologically (Fantin et al., 2006; Le et al., 2010; Shim et al., 1997), leading to development of LDHA inhibitors (Boudreau et al., 2016), but none progressed to clinical trials, suggesting either…”
Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. (2011, neutral): “However, it is now clear that respiration is not impaired in most cancer cells (Fantin et al 2006, Moreno-Sanchez et al 2007, Zu & Guppy 2004).”
Flavonoids as Anticancer Agents (2020, background): “In tumor cells, mitochondria are usually hyperpolarized, and their membrane potential reaches 220 mV [186,187] making them resistant to cell death signaling.”
Oncogenic BRAF regulates oxidative metabolism via PGC1α and MITF (2013, positive): “Similarly, suppression of glycolysis by inhibiting conversion of pyruvate to lactate enhances oxidative phosphorylation and suppressed the growth of breast cancer cell lines (Fantin et al., 2006; Bonnet et al., 2007).”
Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. (2007, background): “Recent evidence indicates that increased glycolysis is a consequence of oncogenic transformation and is advantageous to tumor growth and survival (Fantin et al., 2006; Matoba et al., 2006).”
Targeting mitochondria for cancer therapy (2010, methodology): “Inhibition of lactate dehydrogenase A ( LDHA ) is an alternative strategy to target aerobic glycolysis in cancer cell”
Malignant astrocytic glioma: genetics, biology, and paths to treatment. (2007, background): “In addition to these maladapted biophysical properties of GBM microvasculature, specific genetic mutations in GBM likely contribute to compromised tumor bioener-getics, specifically the shift in energy reduction from oxidative phosphorylation to glycolysis (Elstrom et al. 2004; Fantin et al. 2006).”
The Warburg Effect: How Does it Benefit Cancer Cells? (2016, background): “Nevertheless, it remained unclear whether the Warburg Effect was a bystander in cancer pathogenesis until more recently, when genetic and pharmacological studies conclusively showed that the Warburg Effect was required for tumor growth [11,12].”
MYC on the Path to Cancer (2012, background): “Myc target genes such as ornithine decarboxylase (ODC), lactate dehydrogenase A (LDHA), and glutaminase (GLS) have also been targeted by shRNAs or drug-like small molecules in vivo (Figure 3) (Fantin et al., 2006; Le et al., 2010, 2012; Seltzer et al., 2010; Seth et al., 2011; Wang et al., 2010; Xie”
Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer (2008, background): “This hypothesis is also supported by the recently published work that inhibition of LDH (by siRNA), which promotes the transfer of pyruvate into the mitochondria (in that sense mimicking DCA), also promotes cancer apoptosis and decreases tumour growth in vitro and in mice xenotransplants (”