title: Inhibition of Aerobic Glycolysis Represses Akt/mTOR/HIF-1α Axis and Restores Tamoxifen Sensitivity in Antiestrogen-Resistant Breast Cancer Cells.
abstract: 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.
authors.affiliation: Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon Road, Yongsan-gu, Seoul, Republic of Korea.
authors.forename: Yu Mi
authors.initials: YM
authors.lastname: Woo
authors.affiliation: Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon Road, Yongsan-gu, Seoul, Republic of Korea.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Shin
authors.affiliation: Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon Road, Yongsan-gu, Seoul, Republic of Korea.
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon Road, Yongsan-gu, Seoul, Republic of Korea.
authors.forename: Sunyoung
authors.initials: S
authors.lastname: Lee
authors.affiliation: National Research Laboratory for Mitochondrial Signaling Laboratory, Cardiovascular and Metabolic Disease Center, Department of Physiology, College of Medicine, Department of Health Sciences and Technology, Graduate School, Inje University, Gaegume 2 dong, Busanjin-gu, Busan.
authors.forename: Seung Hun
authors.initials: SH
authors.lastname: Jeong
authors.affiliation: Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon Road, Yongsan-gu, Seoul, Republic of Korea.
authors.forename: Hyun Kyung
authors.initials: HK
authors.lastname: Kong
authors.affiliation: Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon Road, Yongsan-gu, Seoul, Republic of Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Park
authors.affiliation: National Research Laboratory for Mitochondrial Signaling Laboratory, Cardiovascular and Metabolic Disease Center, Department of Physiology, College of Medicine, Department of Health Sciences and Technology, Graduate School, Inje University, Gaegume 2 dong, Busanjin-gu, Busan.
authors.forename: Hyoung Kyu
authors.initials: HK
authors.lastname: Kim
authors.affiliation: National Research Laboratory for Mitochondrial Signaling Laboratory, Cardiovascular and Metabolic Disease Center, Department of Physiology, College of Medicine, Department of Health Sciences and Technology, Graduate School, Inje University, Gaegume 2 dong, Busanjin-gu, Busan.
authors.forename: Jin
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Medical and Pharmaceutical Sciences, Sookmyung Women's University, 52 Hyochangwon Road, Yongsan-gu, Seoul, Republic of Korea, Korea.
authors.forename: Minsun
authors.initials: M
authors.lastname: Chang
authors.affiliation: Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon Road, Yongsan-gu, Seoul, Republic of Korea.
authors.forename: Jong-Hoon
authors.initials: JH
authors.lastname: Park
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000332:Aerobiosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D005260:Female; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects* / Q000235:genetics; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007773:Lactates / Q000378:metabolism; D061986:MCF-7 Cells; D009154:Mutation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D004272:DNA, Mitochondrial; D020847:Estrogen Receptor Modulators; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007773:Lactates; D017382:Reactive Oxygen Species; D013629:Tamoxifen; D006593:Hexokinase; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose