Suppression of ovarian cancer by low-intensity ultrasound through depletion of IL-6/STAT3 inflammatory pathway-maintained cancer stemness

Abstract

Ovarian carcinoma is the key cause of cancer death from gynecological malignancy of women. Chemotherapy-resistance, metastasis and relapse contribute to the high mortality in ovarian cancer patients. Cancer stem cells (CSCs) stand for the root of kinds of cancer types such as ovarian cancer, are the key driver of tumor initiation, cancer metastasis, and resistance to conventional chemotherapy as well as genomic targeted therapy. Thus, the approach to eliminate CSCs and uncovering the mechanism will have substantial impact on cancer therapy. However, targeting CSC remains unfeasible in clinical practice in ovarian cancer therapy. In this study, we first found that Low-intensity ultrasound (LIUS) was capable of reducing the CSC populations in the xenograft model with ovarian cancer, with blocking survival, anti-apoptosis, self-renewal, and downregulating the cancer stemness genes in ovarian CSCs. Moreover, LIUS ameliorated IL-6/STAT3 inflammatory pathway via inhibiting IL-6-induced STAT3 phosphorylation, DNA binding activity and, the expressions of its downstream effectors in ovarian CSCs while no explicit effect was found in the corresponding bulk cancer cells. Additional approaches in molecular studies showed that LIUS disrupts CSC features via inhibiting IL-6/STAT3 inflammatory pathway. Collectively, our data for the first time elucidate IL-6/STAT3 inflammatory loop as the key CSC or cancer stemness pathway in ovarian cancer by LIUS treatment, providing a novel and potential therapy and a promising target in ovarian cancer.