Abstract
Propionate is a short-chain fatty acid (SCFA) mainly produced from carbohydrates by gut microbiota. Sodium propionate (SP) has shown to suppress the invasion in G protein-coupled receptor 41 (GPR41) and GPR43-overexpressing breast cancer cells. In this study we investigated the effects of SP on the proliferation, apoptosis, autophagy, and antioxidant production of breast cancer cells. We showed that SP (5−20 mM) dose-dependently inhibited proliferation and induced apoptosis in breast cancer cell lines JIMT-1 (ER-negative and HER2-expressing) and MCF7 (ER-positive type), and this effect was not affected by PTX, thus not mediated by the GPR41 or GPR43 SCFA receptors. Meanwhile, we demonstrated that SP treatment increased autophagic and antioxidant activity in JIMT-1 and MCF7 breast cancer cells, which might be a compensatory mechanism to overcome SP-induced apoptosis, but were not sufficient to overcome SP-mediated suppression of proliferation and induction of apoptosis. We revealed that the anticancer effect of SP was mediated by inhibiting JAK2/STAT3 signaling which led to cell-cycle arrest at G0/G1 phase, and increasing levels of ROS and phosphorylation of p38 MAPK which induced apoptosis. In nude mice bearing JIMT-1 and MCF7 cells xenograft, administration of SP (20 mg/mL in drinking water) significantly suppressed tumor growth by regulating STAT3 and p38 in tumor tissues. These results suggest that SP suppresses proliferation and induces apoptosis in breast cancer cells by inhibiting STAT3, increasing the ROS level and activating p38. Therefore, SP is a candidate therapeutic agent for breast cancer.
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Acknowledgements
This work was supported by the National Research Foundation of Korea (KRF), funded by the Ministry of Science and ICT (grant no. NRF-2018R1A2A2A05023578).
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JHH, HSP, KSH, and CSM designed the study, analyzed the data, and wrote the manuscript. JHH, KSH, and CSM revised the manuscript. JHH, HSP, JWP, DHL, KWJ, and ML performed the experiments and analyzed the data.
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Park, HS., Han, JH., Park, J.W. et al. Sodium propionate exerts anticancer effect in mice bearing breast cancer cell xenograft by regulating JAK2/STAT3/ROS/p38 MAPK signaling. Acta Pharmacol Sin 42, 1311–1323 (2021). https://doi.org/10.1038/s41401-020-00522-2
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DOI: https://doi.org/10.1038/s41401-020-00522-2
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