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.
Highlights
Most tumors that initially respond to tamoxifen eventually acquire resistance to it in 2 to 5 years and acquired tamoxifen resistance is a critical therapeutic problem [1,2,3]
The levels of lactate produced via the aerobic glycolysis of 13C6-glucose labeled glucose were monitored using 1D and 2D 1H nuclear magnetic resonance (NMR) methods to assess if the tamoxifen-resistant breast cancer cells had a higher rate of aerobic glycolysis
Our study reports that tamoxifen-resistant breast cancer cells display altered glycolysis compared to tamoxifen-sensitive cells and Akt/mTOR and AMPK signaling molecules are attributed to hypoxia-inducible factor (HIF)-1α-regulated glucose metabolism in these cells
Summary
Most tumors that initially respond to tamoxifen eventually acquire resistance to it in 2 to 5 years and acquired tamoxifen resistance is a critical therapeutic problem [1,2,3]. It has been observed that the levels of lactate as the end products of glycolysis are higher in aggressive cancer cells such as drug-resistant or metastatic cancers [10,11], which implies that the Warburg effect in these cancers may reflect metabolic adaptations associated with the development of resistance to chemotherapeutic agents such as doxorubicin, cytosine arabinoside, taxol, cisplatin, and vincristine [12,13,14,15,16]. No studies have shown the potential role of glycolytic metabolism in the development of tamoxifen resistance
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