Involvement of the P2X7 receptor in the migration and metastasis of tamoxifen-resistant breast cancer: effects on small extracellular vesicles production

Abstract

Tamoxifen (TAM) is the standard anti-hormonal therapy for estrogen receptor-positive breast cancer. However, long-term TAM therapy can make acquisition of TAM resistance and there are still no solutions to treat TAM-resistant breast cancer. In this study, we found that protein and mRNA expression of the P2X purinoreceptor 7 (P2X7) was higher in tamoxifen resistant MCF-7 (TAMR-MCF-7) cells than in control MCF-7 cells. P2X7 inhibition potently inhibited the migration of TAMR-MCF-7 cells and the liver metastasis burden of TAMR-MCF-7 cells in the spleen-liver metastasis experiment. However, the P2X7 antagonist did not affect protein expression of matrix metalloproteinase (MMP)-2, MMP-9, and epithelial-mesenchymal transition markers. Here our data indicate a link between small extracellular vesicles (sEV) and P2X7, and suggest a new mechanism of metastasis in TAM-resistant breast cancer cells through P2X7 receptors. The migration of TAMR-MCF-7 cells was increased in a concentration-dependent manner by purified sEV treatment. The number of secreted sEVs and the protein levels of CD63 in TAMR-MCF-7 cells were decreased by the P2X7 antagonist, showing that P2X7 influences the production of sEV. Our results suggest that inhibiting the P2X7 could be considered for metastasis prevention in TAM-resistant cancer patients.

Identification and Semi-Synthesis of 3-O-Protocatechuoylceanothic Acid, a Novel and Natural GPR120 Agonist †

“…GPR120 as a GPCR is mainly coupled with Gαq protein [3,4,5]. To investigate the GPR120 agonist activities of the isolated 25 triterpenoids, we examined the Gαq-mediated intracellular calcium ([Ca 2+ ]i) release after exposing hGPR120-CHO cells to a known GPR120 agonist, GW-9508, or to the isolated components (Figure 2a) [18]. The intracellular calcium ([Ca 2+ ]i) was significantly increased by five natural triterpenoids, namely, S4 , S7 , S12 , 3- O -Protocatechuoylceanothic acid ( 1 ) , and S16 ; the other components did not have any significant effects.…”

“…The increase in GPR120-mediated intracellular Ca 2+ was measured by the [Ca 2+ ] FLIPR assay as described previously [18]. Briefly, CHO cells overexpressing hGPR120 (hGPR120-CHO) and Gα16 (Gα16-CHO) were seeded (5 × 10 4 cells of each type) in 96-well plates and cultured overnight.…”

Curcumin attenuates lncRNA H19‑induced epithelial‑mesenchymal transition in tamoxifen‑resistant breast cancer cells

“…Although the initial response to tamoxifen is satisfactory, the majority of patients develop resistance and tumor progression (5). Moreover, tamoxifen-resistant (TAMR) breast cancer is more prone to invasion and metastasis (6), thus the 5-year survival rate of patients with breast cancer drops from 80 to 27% with the occurrence of distant metastasis (7).…”

P2X7 blockade inhibits the growth of breast cancer in 4T1 breast cancer-bearing mice by NLRP3/caspase 1 pathway

“…Recent studies [10][11][12] have shown that extracellular ATP is likely to be an important invasive factor in TME. The ATP-gated receptor P2X7 is expressed in multiple malignant tumours, including breast cancers [13]. Furthermore, it has been reported that P2X7R is the key mediator of ATP to promote the invasion of cancer growths [14].…”