Role of monocarboxylate transporter I/lactate dehydrogenase B-mediated lactate recycling in tamoxifen-resistant breast cancer cells

by Selleckchem | Jan 31 2024

Although tamoxifen (TAM) is widely used in patients with estrogen receptor-positive breast cancer, the development of tamoxifen resistance is common. The previous finding suggests that the development of tamoxifen resistance is driven by epiregulin or hypoxia-inducible factor-1α-dependent glycolysis activation. Nonetheless, the mechanisms responsible for cancer cell survival and growth in a lactic acid-rich environment remain elusive. We found that the growth and survival of tamoxifen-resistant MCF-7 cells (TAMR-MCF-7) depend on glycolysis rather than oxidative phosphorylation. The levels of the glycolytic enzymes were higher in TAMR-MCF-7 cells than in parental MCF-7 cells, whereas the mitochondrial number and complex I level were decreased. Importantly, TAMR-MCF-7 cells were more resistant to low glucose and high lactate growth conditions. Isotope tracing analysis using 13C-lactate confirmed that lactate conversion to pyruvate was enhanced in TAMR-MCF-7 cells. We identified monocarboxylate transporter1 (MCT1) and lactate dehydrogenase B (LDHB) as important mediators of lactate influx and its conversion to pyruvate, respectively. Consistently, AR-C155858 (MCT1 inhibitor) inhibited the proliferation, migration, spheroid formation, and in vivo tumor growth of TAMR-MCF-7 cells. Our findings suggest that TAMR-MCF-7 cells depend on glycolysis and glutaminolysis for energy and support that targeting MCT1- and LDHB-dependent lactate recycling may be a promising strategy to treat patients with TAM-resistant breast cancer.

Comments:

It sounds like you're summarizing a research study or paper that explores the mechanisms behind tamoxifen resistance in breast cancer cells and highlights the reliance of tamoxifen-resistant MCF-7 cells on glycolysis, particularly their dependence on lactate metabolism for survival and growth.

The findings suggest that tamoxifen-resistant MCF-7 cells exhibit higher levels of glycolytic enzymes and increased lactate conversion to pyruvate compared to parental MCF-7 cells. Additionally, the decrease in mitochondrial number and complex I level in the resistant cells indicates a shift away from oxidative phosphorylation towards reliance on glycolysis.

Monocarboxylate transporter 1 (MCT1) and lactate dehydrogenase B (LDHB) have been identified as key players in mediating lactate influx and its conversion to pyruvate, respectively, in these tamoxifen-resistant cells. Inhibition of MCT1 using AR-C155858 showed promise in inhibiting various aspects of TAMR-MCF-7 cell behavior, such as proliferation, migration, spheroid formation, and tumor growth in vivo.

Overall, the study suggests that targeting the pathways involving MCT1 and LDHB, specifically focusing on lactate recycling, might offer a promising strategy for treating patients with tamoxifen-resistant breast cancer.

This research adds to the understanding of how cancer cells adapt to become resistant to tamoxifen and highlights potential avenues for therapeutic intervention by disrupting their reliance on glycolysis and lactate metabolism.