Abstract
Background: Breast cancer is the most common malignancy in women worldwide. P2X7 is a transmembrane receptor expressed in breast cancer and activated by the ATP tumor microenvironment, driving cell proliferation, angiogenesis, and metastasis via different signaling pathways. The role of the P2X7 receptor, hypoxia, and autophagy in regulating tumor progression is controversial. The multikinase inhibitor regorafenib prevents the activation of numerous kinases involved in angiogenesis, proliferation, and metastasis. The present study aimed to evaluate the modulatory effect of regorafenib on the hypoxia/angiogenesis/P2X7R/autophagy axis on the MCF7 breast cancer cell line and its impact on different signaling pathways involved in breast cancer pathogenesis. Methods: The levels of VEGF, VEGFR, PI3K, NF-κB, HIF-1α, and LC3-II were analyzed using ELISA, and caspase-3 activity was also assessed colorimetrically. Phosphorylated (p)-p38 MAPK and purinergic ligand-gated ion channel 7 (P2X7) receptor protein expression levels were analyzed via Western blotting. Reverse transcription-quantitative PCR was used to determine the mRNA expression levels of Beclin 1 (BECN1), LC3-II, and sequestosome 1 (p62). Results: Regorafenib reduced MCF7 cell viability in a dose-dependent manner. Furthermore, regorafenib significantly reduced levels of PI3K, NF-κB, VEGF, VEGFR, P2X7 receptor, and p-p38 MAPK protein expression, and markedly reduced p62 mRNA expression levels. However, regorafenib significantly increased caspase-3 activity, as well as BECN1 and LC3-II mRNA expression levels. Conclusions: Regorafenib was demonstrated to possibly exhibit antitumor activity on the breast cancer cell line via modulation of the P2X7/HIF-1α/VEGF, P2X7/P38, P2X7/ERK/NF-κB, and P2X7/beclin 1 pathways.
Highlights
Breast cancer is one of the most common cancers worldwide, and is the main leading cause of cancer mortality in women [1]
The present study aimed to evaluate the modulatory effect of regorafenib on the P2X7/hypoxia-inducible factor-1 α (HIF-1α)/VEGF, P2X7/P38, P2X7/ERK/NF-κB, and P2X7/beclin 1 pathways on the MCF7 breast cancer cell line and its impact on different signaling pathways involved in breast cancer progression
The results demonstrated that the cytotoxic effect of regorafenib on MCF7 cells was concentration-dependent, with an IC50 of 8.39 ± 0.43 μM (Figure 1)
Summary
Breast cancer is one of the most common cancers worldwide, and is the main leading cause of cancer mortality in women [1]. Angiogenesis, autophagy, and apoptosis serve essential roles in breast cancer progression via numerous signaling pathways [2,3,4]. Apoptosis and autophagy are common types of programmed cell death, and their malfunction can contribute to tumor growth [8]. Targeting apoptosis and autophagy via numerous signaling pathways, including the PI3K signaling pathway, has served a major role in cancer therapeutic development [12,13]. The present study aimed to evaluate the modulatory effect of regorafenib on the P2X7/HIF-1α/VEGF, P2X7/P38, P2X7/ERK/NF-κB, and P2X7/beclin 1 pathways on the MCF7 breast cancer cell line and its impact on different signaling pathways involved in breast cancer progression
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