Resveratrol is an inhibitor of sodium‐dependent inorganic phosphate transport in triple‐negative MDA‐MB‐231 breast cancer cells

Abstract

Metastasis is a major cause of death in patients with breast cancer. A growing body of evidence has demonstrated the antitumour effects of resveratrol, a non-flavonoid polyphenol. Resveratrol inhibits metastatic processes, such as the migration and invasion of cancer cells. In several cancer types, the importance of inorganic phosphate (Pi) for tumor progression has been demonstrated. The metastatic process in breast cancer is associated with Na + -dependent Pi transporters. In this study, we demonstrate, for the first time, that resveratrol inhibits the Na + -dependent Pi transporter. Results from kinetic analysis shows that resveratrol inhibits Na +dependent Pi transport non-competitively. Resveratrol also inhibits adhesion/migration in MDA-MB-231 cells, likely related to inhibition of the Na + -dependent Pi transporter.

Hydrogen Peroxide Generation as an Underlying Response to High Extracellular Inorganic Phosphate (Pi) in Breast Cancer Cells

“…The comparison of transcription levels of SLCs Pi transporters in MCF-7, MDA-MB-231, and MCF-10 cells, shows that Na + PiIIb is the principal transporter responsible for Na + :Pi uptake in all cells (Table S1 and Figure S1). In a previous study, our group demonstrated that MDA-MB-231 cells, after 24 h treatment with 2 mM Pi, showed inhibition of Na + -dependent Pi transport and, in a compensatory way, increased the H + -dependent Pi transport [33]. Therefore, to understand the effect of high Pi concentrations on breast cancer cell transporters, we measured Na +dependent Pi transport (Figure 1A) and H + -dependent Pi transport (Figure 1B) in breast cell lines: a non-tumoral breast cell, MCF10-A; a luminal A breast cancer cell, MCF-7; and a TNBC cell, MDA-MB-231 in the presence of increasing concentrations of Pi (1, 2, 4 and 8 mM).…”

“…Therefore, it is believed that the tumour cell requires more Pi to supply the energy needs of migration and cell adhesion to ECM. Indeed, the Pi transport plays a fundamental role in stimulating migration and adhesion in high extracellular Pi [6,[31][32][33].…”

“…Before the experiments, cells harvested from the culture medium were washed two times with a buffer consisting of 116 mM NaCl, 5.4 mM KCl, 5.5 mM glucose, 0.8 mM MgCl 2 , and 50 mM HEPES (pH 7.2). Adherent cells were dissociated after incubation at 37 • C and 5% CO 2 with a trypsin solution (2.5 g/L, pH 7.2, 0.05 mL/cm 2 ), and the cell number and protein concentration after Pi treatment were assessed by counting in a Neubauer chamber and the Bradford method, respectively [31][32][33]58].…”

“…In 2019, using the same MDA-MB-231 cells, we characterized a low-affinity H + -dependent Pi transporter related to cell migration and adhesion processes, especially in the presence of high Pi concentrations [32]. A decrease in NaPi-IIb expression and Na + -dependent Pi transport in the presence of 2 mM Pi were shown [32], and as a compensatory mechanism, H + -dependent Pi transport was stimulated [33].…”

Inhibitory Potential of Resveratrol in Cancer Metastasis: From Biology to Therapy

“…Lastly, RES also impacts the transportation of metal ions, consequently influencing cancer cell motility. According to Marco et al, RES was found to inhibit the adhesion/migration of MDA-MB-231 cells by suppressing Na + -dependent inorganic phosphate transporters [92]. Moreover, it was observed that TRPM7-mediated Mg 2+ influx stimulates EMT and promotes cell migration in prostate cancer cells, while RES impairs TRPM7 function, thereby impeding prostate cancer metastasis [93].…”