Ultrasound irradiation inhibits proliferation of cervical cancer cells by initiating endoplasmic reticulum stress-mediated apoptosis and triggering phosphorylation of JNK

Background. Cervical cancer is the 2nd most frequently diagnosed gynecological cancer. Therefore, it is clinically significant to discover an effective anti-cancer approach. Objectives. This study aimed to investigate the effects of low-intensity ultrasound irradiation (USI) on cervical cancer cells and associated mechanisms of cell death. Materials and methods. Normal human cervical HaCaT cells and cervical cancer cell lines C33A, Hela and Siha were cultured and.-rays applied at a dosage of 2.0 Gy/min. The MTT assay was then used to assess viability (proliferation) of HaCaT, C33A, Hela, and Siha cells. Small interfering RNA (siRNA) sequences that silence the glucose-related protein (GRP78) gene were synthesized. Structural changes to cells exposed to USI were observed with scanning electron microscopy. Immunocytochemistry and western blotting were utilized to examine GRP78, C/EBP-homologous protein (CHOP), phosphorylated JNK (p-JNK), and caspase-12 expression in cervical cancer cells. Results. Ultrasound irradiation reduced the viability of cervical cancer cells and increased apoptosis, compared to untreated tumor cells (p < 0.05). This effect was not apparent on HaCaT cells. Ultrasound irradiation also induced formation of apoptotic bodies compared to untreated tumor cells (p < 0.05), and activated endoplasmic reticulum (ER) stress-associated apoptosis compared to untreated tumor cells (p < 0.05), by triggering GRP78, CHOP and caspase-12 expression. Moreover, USI triggered ER stress by upregulating GRP78 expression. Remarkably, USI triggered phosphorylation of JNK compared to untreated tumor cells (p < 0.05). Ultrasound irradiation initiated phosphorylation of JNK by increasing GRP78 expression. Silencing of GRP78 further enhanced the effect of USI on tumor cells. Conclusions. Ultrasound irradiation significantly inhibited proliferation and induced apoptosis of cervical cancer cells by initiating ER stress associated with apoptosis signaling pathways and triggering phosphorylation of JNK.