Yoda1 Enhanced Low-Magnitude High-Frequency Vibration on Osteocytes in Regulation of MDA-MB-231 Breast Cancer Cell Migration

Simple Summary Bone metastasis is a severe complication that contributes significantly to the morbidity and mortality of breast cancer patients. Although mechanical loading was shown to mediate bone remodeling and attenuate metastatic tumor growth, commonly prescribed exercise can be physically challenging for cancer patients. Low-magnitude high-frequency (LMHF) vibration as an exercise alternative enhances bone mineral density while being safe and easy-to-perform. However, vibration alone appears to be insufficient in reducing bone loss caused by breast cancer. Yoda1, an activator of the mechanosensitive Piezo1 channel, provides a potential solution to intensify the effects of LMHF vibration. This study aims to investigate the effects of combined treatment (Yoda1 and LMHF vibration) in regulating osteoclastogenesis and breast cancer cell migration. We confirmed that combining LMHF vibration and Yoda1 reduces the formation of osteoclasts and further inhibits the migration of MDA-MB-231 breast cancer cells. Our data supported the novel strategy to regulate cancer cell migration for high-risk patients. Low-magnitude (<= 1 g) high-frequency (>= 30 Hz) (LMHF) vibration has been shown to enhance bone mineral density. However, its regulation in breast cancer bone metastasis remains controversial for breast cancer patients and elder populations. Yoda1, an activator of the mechanosensitive Piezo1 channel, could potentially intensify the effect of LMHF vibration by enhancing the mechanoresponse of osteocytes, the major mechanosensory bone cells with high expression of Piezo1. In this study, we treated osteocytes with mono- (Yoda1 only or vibration only) or combined treatment (Yoda1 and LMHF vibration) and examined the further regulation of osteoclasts and breast cancer cells through the conditioned medium. Moreover, we studied the effects of combined treatment on breast cancer cells in regulation of osteocytes. Combined treatment on osteocytes showed beneficial effects, including increasing the nuclear translocation of Yes-associated protein (YAP) in osteocytes (488.0%, p < 0.0001), suppressing osteoclastogenesis (34.3%, p = 0.004), and further reducing migration of MDA-MB-231 (15.1%, p = 0.02) but not Py8119 breast cancer cells (4.2%, p = 0.66). Finally, MDA-MB-231 breast cancer cells subjected to the combined treatment decreased the percentage of apoptotic osteocytes (34.5%, p = 0.04) but did not affect the intracellular calcium influx. This study showed the potential of stimulating Piezo1 in enhancing the mechanoresponse of osteocytes to LMHF vibration and further suppressing breast cancer migration via osteoclasts.

Automated summary

The combined treatment of Yoda1 and low-magnitude high-frequency vibration can effectively reduce bone loss caused by bone metastasis, inhibit osteoclast formation, and suppress breast cancer cell migration.