Abstract
Ovarian cancer has a high mortality rate and high resistance to chemotherapy. Thus, many studies are currently assessing the ability of natural products to induce ovarian cancer cell death. A coumarin derivative, 4-methylumbelliferone (4-MU), has been reported to have anti-cancer effects on various cancers, but its effects on ovarian cancer are not fully understood. In this study, we identified the intracellular mechanism underlying the effects of 4-MU on epithelial ovarian cancer cells. Decreased ovarian cancer cell proliferation and an accumulation of cells in the G2/M phase were observed following 4-MU treatment. Moreover, 4-MU interfered with calcium homeostasis; induced endoplasmic reticulum stress in both cell lines; inhibited AKT and S6 phosphorylation; and increased ERK1/2, P38, and JNK phosphorylation. Furthermore, 4-MU and pharmacological inhibitors showed synergic effects in suppressing cell proliferation. Collectively, our current data indicate that antitumor effects of 4-MU could be appropriate for use as a therapeutic agent against epithelial ovarian cancer cells.
Highlights
Ovarian cancer has lower five-year survival rates (47.6%) than other gynecological cancers, such as breast cancer (89.9%) and uterine cancer (81.2%) [1]
According to the FIGO staging system, when ovarian cancer is at stage III or IV, the carcinoma has metastasized to the retroperitoneal lymph nodes, the peritoneum, or a distant organ [3]
The second reason is that ovarian cancer becomes refractory to chemotherapy after recurrence, which lowers the efficacy of therapy
Summary
Ovarian cancer has lower five-year survival rates (47.6%) than other gynecological cancers, such as breast cancer (89.9%) and uterine cancer (81.2%) [1]. Recurrence occurs in a considerable number of ovarian cancer patients, especially in the late stage and about 20–30% of these cancers show resistance to first-line chemotherapies [4]. Coumarin and its derivatives are phytochemicals found extensively in plants They contain benzene and pyrone ring structures and are known to have several biological activities, including antitumor effects [5,6]. The first research about effects of 4-MU on ovarian cancers revealed that 4-MU suppressed synthesis of hyaluronic acid in SKOV-3 human epithelial ovarian cancer cell lines via downregulation of UDP-glucuronic acids and HAS3 expressions [9]. In 2014, Tamura et al reported that 4-MU diminished proliferation and mRNA levels of thymidine phosphorylase (TP) in HRA cell lines involved in serous subtypes and they suggested 4-MU could affect the PI3K/AKT axis because the TP levels are controlled by PI3K/AKT signaling [11,12]. This study aimed to evaluate the cytotoxic and cytostatic effects of 4-MU on the epithelial ovarian cancer cell lines ES2 and OV90 by assessing the following: (1) cell proliferation and cell cycle distribution, (2) intracellular calcium concentration, (3) levels of proteins related to endoplasmic reticulum (ER) stress, and (4) signal transduction
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