University of Louisville

Poster Title

LDH-A as a Potential Therapeutic Target for Non-small Cell Lung Cancer

Institution

University of Louisville

Abstract

Lung cancer is the leading cause of cancer related deaths in both men and women. Despite this alarming statistic, targeted therapies remain elusive. For this reason, there is a need to study cancer cell metabolism in order to find novel therapeutic approaches. Lactate dehydrogenase (LDH) catalyzes the interconversion of pyruvate and lactate. Suppression of LDH-A, a monomer of tetrameric LDH, is thought to cause ROS-mediated apoptosis of non-small cell lung cancer (NSCLC) cells (1). We have characterized the metabolic effects of LDH-A knockdown (KD) in lung cancer metabolism with the use of shRNA in A549 NSCLC cells to gain mechanistic insight into this detrimental effect. 13C6-Glucose and 13C5- 15N2-Glutamine were used as tracers to probe the perturbation of metabolic pathways induced by cells transduced with an anti LDH-A shRNA plasmid. The fate of the carbon and nitrogen isotopes through metabolic pathways was monitored by various analytical techniques including NMR, GC-MS, and FT-ICR-MS. LDH-A KD enhanced the concentration and enrichment of TCA cycle metabolites such as 13C2 isotopologues of malate and fumarate when cells were given labeled glucose, supporting enhanced TCA cycle activity which can lead to increased oxidative phosphorylation. The fate of 13C derived from glutamine suggests increased anaplerosis to the TCA cycle from glutaminase. The increased TCA cycle activity as a result of LDH-A knockdown may account for the previously observed increase in ROS production which, in turn, leads to cell death (1). This work was supported by the University of Louisville Cancer Education Program NIH/NCI (R25- CA134283) and by funds to Seth Laboratory from Beth Israel Deaconess Medical Center and NCI. 1. Seth P, Grant A, Tang J, Vinogradov E, Wang X, Lenkinski R, Sukhatme VP. On-target inhibition of tumor fermentative glycolysis as visualized by hyperpolarized pyruvate. Neoplasia 2011;13(1):60-71.

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LDH-A as a Potential Therapeutic Target for Non-small Cell Lung Cancer

Lung cancer is the leading cause of cancer related deaths in both men and women. Despite this alarming statistic, targeted therapies remain elusive. For this reason, there is a need to study cancer cell metabolism in order to find novel therapeutic approaches. Lactate dehydrogenase (LDH) catalyzes the interconversion of pyruvate and lactate. Suppression of LDH-A, a monomer of tetrameric LDH, is thought to cause ROS-mediated apoptosis of non-small cell lung cancer (NSCLC) cells (1). We have characterized the metabolic effects of LDH-A knockdown (KD) in lung cancer metabolism with the use of shRNA in A549 NSCLC cells to gain mechanistic insight into this detrimental effect. 13C6-Glucose and 13C5- 15N2-Glutamine were used as tracers to probe the perturbation of metabolic pathways induced by cells transduced with an anti LDH-A shRNA plasmid. The fate of the carbon and nitrogen isotopes through metabolic pathways was monitored by various analytical techniques including NMR, GC-MS, and FT-ICR-MS. LDH-A KD enhanced the concentration and enrichment of TCA cycle metabolites such as 13C2 isotopologues of malate and fumarate when cells were given labeled glucose, supporting enhanced TCA cycle activity which can lead to increased oxidative phosphorylation. The fate of 13C derived from glutamine suggests increased anaplerosis to the TCA cycle from glutaminase. The increased TCA cycle activity as a result of LDH-A knockdown may account for the previously observed increase in ROS production which, in turn, leads to cell death (1). This work was supported by the University of Louisville Cancer Education Program NIH/NCI (R25- CA134283) and by funds to Seth Laboratory from Beth Israel Deaconess Medical Center and NCI. 1. Seth P, Grant A, Tang J, Vinogradov E, Wang X, Lenkinski R, Sukhatme VP. On-target inhibition of tumor fermentative glycolysis as visualized by hyperpolarized pyruvate. Neoplasia 2011;13(1):60-71.