Abstract
Ovarian cancer is the most lethal gynaecological malignancy. Recurrence and subsequent resistance to chemotherapy have become major obstacles to treating these diseases. In the present study, we showed that a natural withanolide isolated from the plant Physalis pubescens L. (Solanaceae), Physapubescin B, exhibited potent anti-tumor activity against ovarian cancer cells. Physapubescin B promoted apoptosis, induced cell-cycle arrest and inhibited invasion of ES-2 and A2780 cells. Physapubescin B treatment also resulted in suppression of the transcriptional activity of STAT3, an oncogenic transcription factor activated in many human malignancies including ovarian cancer, through disturbing the dimerization of STAT3, and thereby inhibited the nuclear translocation of Tyr705/Ser727-phosphorylated STAT3. The IL-6-stimulated activation of STAT3 and its downstream genes Cyclin D1, survivin, and Bcl-xL was also repressed by Physapubescin B. Furthermore, Physapubescin B sensitizes A2780 cells to taxol-induced cell growth inhibition in vitro. These findings strongly suggest that Physapubescin B has potential antitumor activity and may circumvent taxol resistance in human ovarian cancer cells through inhibition of aberrant activation of STAT3.
Highlights
Ovarian cancer (OC) is the 9th most common cancer and the most lethal gynaecological malignancy in the female population [1,2]
Physapubescin B sensitizes A2780 cells to taxol-induced cell growth inhibition in vitro. These findings strongly suggest that Physapubescin B has potential antitumor activity and may circumvent taxol resistance in human ovarian cancer cells through inhibition of aberrant activation of Signal transducer and activator of transcription 3 (STAT3)
We explored the cytotoxic effects of Physapubescin B against OC cells and checked the involvement of STAT3 signaling in this process
Summary
Ovarian cancer (OC) is the 9th most common cancer and the most lethal gynaecological malignancy in the female population [1,2]. Constitutive activation of STAT3 is causally linked to tumor development and progression in various types of solid malignancies, including head and neck cancer, myeloma, prostate cancer, breast cancer, colon cancer, and ovarian cancer [11,12,13,14] It has been observed in 94% of OCs and correlates with recurrence and poor prognosis [15]. Recent studies have shown that aberrant STAT3 activation was closely related with cell growth, cell cycle progression, invasion and drug resistance of ovarian cancer cells [3, 16,17,18] These findings indicate that STAT3 may represent a promising molecular target of gene therapy for OCs
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