Low frequency ultrasound enhances chemotherapy sensitivity and induces autophagy in human paclitaxel resistance prostate cancer PC-3R cells through the ERs-mediated PI3K/Akt/mTOR signaling pathway

Sonodynamic therapy (SDT) as an emerging tumor-assisting method has attracted a great deal of interest in tumor therapy research in recent years. However, autophagy has been observed in several cancer cells treated with SDT and its role and mechanism are not clear. In the present study, we have investigated the effect of low frequency ultrasound on paclitaxel(PTX) resistance prostate cancer PC-3R cells and demonstrated that low frequency ultrasound could induce cancer cell apoptosis, inhibit the expression of multiple drug resistance genes (MRP3, MRP7 and P-glycoprotein) and reverse drug resistance; we further found that low frequency ultrasound induced autophagy in PC-3R cells. Our results demonstrated that low frequency ultrasound enhanced chemotherapy sensitivity and induced autophagy in PC-3R cells by inhibiting the PI3K/AKT/mTOR pathway. Moreover, we observed that low frequency ultrasound-induced cell autophagy was correlated with endoplasmic reticulum stress (ERs). 4-phenylbutyric acid (4-PBA) -mediated protection against ERs clearly implicated ERs in the activation of autophagy and cell apoptosis. In addition, the results showed that ERs served as an upstream effector of the PI3K/AKT/mTOR pathway. More importantly, we observed that inhibition of low frequency ultrasound-induced autophagy enhanced ERs and improved the role of low frequency ultrasound in reversing drug resistance. Over all, our findings provide new insights into the molecular mechanisms underlying low frequency ultrasound-mediated reversal of drug resistance and autophagy in PC-3R cells and support autophagy as a potential agent for enhancing anti-cancer effect of SDT.