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Inhibition of Aerobic Glycolysis Represses Akt/mTOR/HIF-1α Axis and Restores Tamoxifen Sensitivity in Antiestrogen-Resistant Breast Cancer Cells.
PLoS One 2015; 10(7):e0132285Plos

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+Show Affiliations

Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon Road, Yongsan-gu, Seoul, Republic of Korea.Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon Road, Yongsan-gu, Seoul, Republic of Korea.Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon Road, Yongsan-gu, Seoul, Republic of Korea.Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon Road, Yongsan-gu, Seoul, Republic of Korea.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.Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon Road, Yongsan-gu, Seoul, Republic of Korea.Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon Road, Yongsan-gu, Seoul, Republic of Korea.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.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.Department of Medical and Pharmaceutical Sciences, Sookmyung Women's University, 52 Hyochangwon Road, Yongsan-gu, Seoul, Republic of Korea, Korea.Department of Life Systems, Sookmyung Women's University, 52 Hyochangwon Road, Yongsan-gu, Seoul, Republic of Korea.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26158266

Citation

Woo, Yu Mi, et al. "Inhibition of Aerobic Glycolysis Represses Akt/mTOR/HIF-1α Axis and Restores Tamoxifen Sensitivity in Antiestrogen-Resistant Breast Cancer Cells." PloS One, vol. 10, no. 7, 2015, pp. e0132285.
Woo YM, Shin Y, Lee EJ, et al. Inhibition of Aerobic Glycolysis Represses Akt/mTOR/HIF-1α Axis and Restores Tamoxifen Sensitivity in Antiestrogen-Resistant Breast Cancer Cells. PLoS ONE. 2015;10(7):e0132285.
Woo, Y. M., Shin, Y., Lee, E. J., Lee, S., Jeong, S. H., Kong, H. K., ... Park, J. H. (2015). Inhibition of Aerobic Glycolysis Represses Akt/mTOR/HIF-1α Axis and Restores Tamoxifen Sensitivity in Antiestrogen-Resistant Breast Cancer Cells. PloS One, 10(7), pp. e0132285. doi:10.1371/journal.pone.0132285.
Woo YM, et al. Inhibition of Aerobic Glycolysis Represses Akt/mTOR/HIF-1α Axis and Restores Tamoxifen Sensitivity in Antiestrogen-Resistant Breast Cancer Cells. PLoS ONE. 2015;10(7):e0132285. PubMed PMID: 26158266.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of Aerobic Glycolysis Represses Akt/mTOR/HIF-1α Axis and Restores Tamoxifen Sensitivity in Antiestrogen-Resistant Breast Cancer Cells. AU - Woo,Yu Mi, AU - Shin,Yubin, AU - Lee,Eun Ji, AU - Lee,Sunyoung, AU - Jeong,Seung Hun, AU - Kong,Hyun Kyung, AU - Park,Eun Young, AU - Kim,Hyoung Kyu, AU - Han,Jin, AU - Chang,Minsun, AU - Park,Jong-Hoon, Y1 - 2015/07/09/ PY - 2015/01/08/received PY - 2015/06/11/accepted PY - 2015/7/10/entrez PY - 2015/7/15/pubmed PY - 2016/4/19/medline SP - e0132285 EP - e0132285 JF - PloS one JO - PLoS ONE VL - 10 IS - 7 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/26158266/Inhibition_of_Aerobic_Glycolysis_Represses_Akt/mTOR/HIF_1α_Axis_and_Restores_Tamoxifen_Sensitivity_in_Antiestrogen_Resistant_Breast_Cancer_Cells_ L2 - http://dx.plos.org/10.1371/journal.pone.0132285 DB - PRIME DP - Unbound Medicine ER -