Inhibition of Aerobic Glycolysis Represses Akt/mTOR/HIF-1α Axis and Restores Tamoxifen Sensitivity in Antiestrogen-Resistant Breast Cancer Cells

• Published in: PloS one Vol. 10; no. 7; p. e0132285
• Main Authors: Woo, Yu Mi, Shin, Yubin, Lee, Eun Ji, Lee, Sunyoung, Jeong, Seung Hun, Kong, Hyun Kyung, Park, Eun Young, Kim, Hyoung Kyu, Han, Jin, Chang, Minsun, Park, Jong-Hoon
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.07.2015; Public Library of Science (PLoS)
• Subjects: Aerobiosis; AKT protein; AMP-Activated Protein Kinases - metabolism; Antiestrogens; Blotting, Western; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cell Line, Tumor; Cell survival; Chemotherapy; DNA, Mitochondrial - genetics; Drug resistance; Drug Resistance, Neoplasm - drug effects; Energy; Enzymes; Estrogen Receptor Modulators - pharmacology; Estrogens; Female; Genes; Glucose; Glucose - metabolism; Glycolysis; Glycolysis - drug effects; Glycolysis - genetics; Growth rate; Health sciences; Hexokinase; Hexokinase - genetics; Hexokinase - metabolism; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Inhibition; Kinases; Laboratories; Lactates - metabolism; Lactic acid; MCF-7 Cells; Metabolic disorders; Metabolites; Mutation; Physiology; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Reactive Oxygen Species - metabolism; Restoration; RNA Interference; Signal transduction; Signal Transduction - drug effects; Signaling; Studies; Tamoxifen; Tamoxifen - pharmacology; TOR protein; TOR Serine-Threonine Kinases - metabolism; Tumor cell lines; Womens health
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0132285

Tamoxifen resistance is often observed in the majority of estrogen receptor-positive breast cancers and it remains as a serious clinical problem in breast cancer management. Increased aerobic glycolysis has been proposed as one of the mechanisms for acquired resistance to chemotherapeutic agents in breast cancer cells such as adriamycin. Herein, we report that the glycolysis rates in LCC2 and LCC9--tamoxifen-resistant human breast cancer cell lines derived from MCF7--are higher than those in MCF7S, which is the parent MCF7 subline. Inhibition of key glycolytic enzyme such as hexokinase-2 resulted in cell growth retardation at higher degree in LCC2 and LCC9 than that in MCF7S. This implies that increased aerobic glycolysis even under O2-rich conditions, a phenomenon known as the Warburg effect, is closely associated with tamoxifen resistance. We found that HIF-1α is activated via an Akt/mTOR signaling pathway in LCC2 and LCC9 cells without hypoxic condition. Importantly, specific inhibition of hexokinase-2 suppressed the activity of Akt/mTOR/HIF-1α axis in LCC2 and LCC9 cells. In addition, the phosphorylated AMPK which is a negative regulator of mTOR was decreased in LCC2 and LCC9 cells compared to MCF7S. Interestingly, either the inhibition of mTOR activity or increase in AMPK activity induced a reduction in lactate accumulation and cell survival in the LCC2 and LCC9 cells. Taken together, our data provide evidence that development of tamoxifen resistance may be driven by HIF-1α hyperactivation via modulation of Akt/mTOR and/or AMPK signaling pathways. Therefore, we suggest that the HIF-1α hyperactivation is a critical marker of increased aerobic glycolysis in accordance with tamoxifen resistance and thus restoration of aerobic glycolysis may be novel therapeutic target for treatment of tamoxifen-resistant breast cancer.