Inhibition of the Warburg effect with a natural compound reveals a novel measurement for determining the metastatic potential of breast cancers
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Ritu Arora1, David Schmitt1, Balasubramanyam Karanam2, Ming Tan1, Clayton Yates2, Windy Dean-Colomb1,3
1Department of Oncologic Sciences, University of South Alabama Mitchell Cancer Institute, Mobile, AL 36604, USA
2Department of Biology and Center for Cancer Research, Tuskegee University, Tuskegee, AL 36088, USA
3Department of Oncologic Research, University Hospital and Clinics, Lafayette General Health, Lafayette, LA 70503, USA
Windy Dean-Colomb, e-mail: [email protected]
Keywords: Warburg effect, Metabolism, Panepoxydone, LDH-A, LDH-B, Breast cancer
Received: August 15, 2014 Accepted: November 02, 2014 Published: January 07, 2015
Metabolism is an important differentiating feature of cancer cells. Lactate dehydrogenases (LDH) A/B are metabolically important proteins and are involved in the critical step of inter-conversion of lactate to pyruvate. Panepoxydone (PP), a natural NF-kB inhibitor, significantly reduces the oxygen consumption and lactate production of MCF-7 and triple negative (MDA-MB-231, MDA-MB-468 and MDA-MB-453) breast cancer cells. We further observed that PP inhibited mitochondrial membrane potential and the ATP synthesis using flow cytometry. PP also up-regulated LDH-B and down-regulated LDH-A expression levels in all breast cancer cells to similar levels observed in HMEC cells. Over-expression of LDH-B in cancer cell lines leads to enhanced apoptosis, mitochondrial damage, and reduced cell migration. Analyzing the patient data set GDS4069 available on the GEO website, we observed 100% of non TNBC and 60% of TNBC patients had less LDH-B expression than LDH-A expression levels. Herein we report a new term called Glycolytic index, a novel method to calculate utilization of oxidative phosphorylation in breast cancer cells through measuring the ratio of the LDH-B to LDH-A. Furthermore, inhibitors of NF-kB could serve as a therapeutic agent for targeting metabolism and for the treatment of triple negative breast cancer.
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