High Glucose Level Promotes Migration Behavior of Breast Cancer Cells through Zinc and Its Transporters

Abstract

BackgroundThe diabetes patients have been associated with an increased risk of mortality by breast cancer and there are difference between the breast cancer patients with diabetes, and their nondiabetic counterparts in the regimen choice and effects of breast cancer treatment. However, the pathophysiological relationships of diabetes and breast cancer have not yet been elucidated in detail. In this study, we investigate the breast cancer cell line, MCF-7 motility, which linked to invasion and metastasis, in high glucose level corresponding to hyperglycemia and the role of Zn and its transporter.Methodology/Principal findingsWe demonstrated the significant motility of MCF-7 cultured in hyperglycemic level (25 mM glucose) in comparison to normal physiological glucose level (5.5 mM glucose). The other hand, the osmotic control medium, 5.5 mM glucose with 19.5 mM mannitol or fructose had no effect on migratory, suggesting that high glucose level promotes the migration of MCF-7. Moreover, the activity of intracellular Zn2+ uptake significantly increased in high glucose-treated cells in comparison to 5.5 mM glucose, and the mRNA expression of zinc transporters, ZIP6 and ZIP10, was upregulated in 25 mM glucose-treated cells. The deficiency of ZIP6 or ZIP10 and intracellular Zn2+ significantly inhibited the high migration activity in 25 mM glucose medium, indicating that Zn2+ transported via ZIP6 and ZIP10 play an essential role in the promotion of cell motility by high glucose stimulation.Conclusion/SignificanceZinc and its transporters, ZIP6 and ZIP10, are required for the motility stimulated with high glucose level. These findings provide the first evidence proposing the novel strategies for the diagnosis and therapy of breast cancer with hyperglycemia.

Potential Roles of GLUT12 for Glucose Sensing and Cellular Migration in MCF-7 Human Breast Cancer Cells Under High Glucose Conditions

“…Scratch wound-healing assays were performed as described previously (13). A confluent monolayer of cells cultured with MEM containing 10% FBS and 5.5 mM D-glucose in a 6-well plate was scratched with a sterile 10 μl pipette tip to create a straight line in each well.…”

“…The presence of a high glucose level, corresponding to hyperglycemia in vivo, has been reported to modulate breast cancer cell functions including survival, growth, and proliferation, suggesting the glucose level as being critical for breast cancer progression in patients with diabetes (11)(12)(13)(14)(15)(16)(17)(18)(19). Our previous studies also demonstrated that the migratory ability of MCF-7 human breast cancer cells, which is linked to invasion and metastasis, was strongly dependent on glucose concentration (13,14). However, the mechanisms responsible for detecting changes of glucose level leading to changes in breast cancer development are largely unknown.…”

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

“…ZIP6 and ZIP10 promote cell motility of breast cancer cells by high glucose stimulation (393). Maternally derived ZIP6 and ZIP10 import zinc into the mammalian oocyte for proper meiotic progression, in which ZIP6 and ZIP10 transcripts are upregulated in a synchronized manner (218).…”

Reciprocal regulation of actin cytoskeleton remodelling and cell migration by Ca2+ and Zn2+: role of TRPM2 channels

“…Unfortunately, little is known about the role of these Zn 2+ -handling proteins in cell migration. One recent study has demonstrated that MCF-7 breast cancer cell migration induced by a high glucose concentration is mediated by the ZIP6-and ZIP10-dependent increase in cytosolic Zn 2+ (Takatani-Nakase et al, 2014). By contrast, there are numerous studies on the role of Ca 2+ channels in cell migration.…”