Abstract
Treatment of advanced ovarian cancer involves platinum-based chemotherapy. However, chemoresistance is a major obstacle. Cancer stem cells (CSCs) are thought to be one of the causes of chemoresistance, but the underlying mechanism remains elusive. Recently, human telomerase reverse transcriptase (hTERT) has been reported to promote CSC-like traits. In this study, we found that a mitotic inhibitor, eribulin mesylate (eribulin), effectively inhibited growth of platinum-resistant ovarian cancer cell lines. Eribulin-sensitive cells showed a higher efficiency for sphere formation, suggesting that these cells possess an enhanced CSC-like phenotype. Moreover, these cells expressed a higher level of hTERT, and suppression of hTERT expression by siRNA resulted in decreased sensitivity to eribulin, suggesting that hTERT may be a target for eribulin. Indeed, we found that eribulin directly inhibited RNA-dependent RNA polymerase (RdRP) activity, but not telomerase activity of hTERT in vitro. We propose that eribulin targets the RdRP activity of hTERT and may be an effective therapeutic option for CSCs. Furthermore, hTERT may be a useful biomarker to predict clinical responses to eribulin.
Highlights
Ovarian cancer is the most lethal of all gynecological malignancies, claiming around 150,000 lives annually worldwide
Fourteen ovarian adenocarcinoma cell lines were investigated for sensitivity to cisplatin [cis-diamminedichloroplatinum(II)], including six Serous adenocarcinoma (SAC) cell lines (PEO1, PEO4, PEO14, PEO23, OVKATE, and OVSAHO), six cell carcinoma (CCC) cell lines (RMG-I, ES-2, OVISE, OVMANA, OVTOKO, and TOV21G), and two undifferentiated/unclassified adenocarcinoma cell lines (OVCAR-3 and A2780) (Table S1)
Since we have recently demonstrated that NS together with human telomerase reverse transcriptase (hTERT) and brahma-related gene 1 (BRG1) maintains Cancer stem cells (CSCs) [8] and we and others have demonstrated that NS is a useful CSC marker [20,21,22], we investigated the expression of BRG1 and NS in Eribulin S and Eribulin R cell lines
Summary
Ovarian cancer is the most lethal of all gynecological malignancies, claiming around 150,000 lives annually worldwide. The majority of ovarian cancers are diagnosed at an advanced stage, and platinum-based chemotherapy is the standard first-line treatment for advanced ovarian cancer patients. Chemoresistance is a major obstacle in treating ovarian cancer. Serous adenocarcinoma (SAC), the most common type of ovarian cancer, usually responds well to initial platinum-based chemotherapy, it will recur and develop drug resistance. Clear cell carcinoma (CCC), the second most common type in Japan, is often resistant to initial platinum-based chemotherapy [1]. Regardless of whether the resistance is acquired or primary, more promising therapeutic strategies are necessary to overcome chemoresistance and improve the prognosis of ovarian cancer patients
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