Abstract
Ovarian cancer is a prevalent female malignancy affecting the health and life of an increasing population of women around the world. Paclitaxel (PTX) resistance is a significant clinical problem in the treatment of ovarian cancer. However, the regulation mechanism of PTX resistance remains unclear. In this investigation, we reported an innovative function of the long noncoding RNA RMRP in promoting PTX resistance and glycolysis of ovarian cancer cells. We observed that RMRP was highly expressed in the ovarian cancer samples, in which the expression of RMRP was elevated in the PTX-resistant patients compared with the PTX-sensitive patients. Meanwhile, RMRP was upregulated in PTX-resistant ovarian cancer cell lines. Functionally, we found that the silencing of RMRP by siRNA significantly enhanced the PTX sensitivity of PTX-resistant ovarian cancer cells, in which the IC50 of PTX was reduced by RMRP depletion. The RMRP knockdown reduced cell viabilities and enhanced cell apoptosis of PTX-resistant ovarian cancer cells. Moreover, we observed that glucose uptake was enhanced in PTX-resistant ovarian cancer cells. The depletion of RMRP decreased glucose uptake, lactate product, and ATP production in PTX-resistant ovarian cancer cells. About the mechanism, we identified that RMRP was able to sponge miR-580-3p to enhance mitochondrial calcium uptake 1 (MICU1) expression in PTX-resistant ovarian cancer cells. MICU1 overexpression and miR-580-3p repression could reverse the RMRP-inhibited proliferation of PTX-resistant ovarian cancer cells in vitro. Thus, we concluded that RMRP contributes to PTX resistance and glycolysis of ovarian cancer by enhancing MICU1 expression through sponging miR-580-3p. Targeting RMRP may serve as a potential therapeutic strategy for the treatment of PTX-resistant ovarian cancer patients.
Highlights
We found an elevated level of RMRP in ovary cancer patients that were resistant to PTX therapy, and the depletion of RMRP could notably suppress glycolysis
Ovarian cancer is a prevalent female malignancy with high recurrence, and PTX resistance is a significant clinical problem. e mechanism underlying the regulation of PTX resistance of ovarian cancer cells remains obscure
We provide new evidence of Long noncoding RNAs (lncRNAs) RMRP contributing to PTX resistance of ovarian cancer cells
Summary
Epithelial ovarian cancer ranks as the most lethal gynecological cancer, severely threatening the quality of life of women around the world [1]. e primary cause of the high lethality is mainly due to the lack of typical early symptoms and screening manners [2]. Epithelial ovarian cancer ranks as the most lethal gynecological cancer, severely threatening the quality of life of women around the world [1]. Most patients with ovarian cancer are not diagnosed until an advanced stage [2]. E global standard of clinical management of ovarian cancer mainly includes surgical operations and chemotherapy [3]. Despite the fast development of therapeutic means, paclitaxel and carboplatin have remained the most prevalent chemotherapy agents for ovarian cancer for the past decades [3]. Tumor recurrence occurs following the long-term administration of chemotherapy drugs due to the development of multidrug resistance (MDR) [1, 3]. Among the developed drug resistance, paclitaxel (PTX) resistance constantly contributes to the failure of ovarian cancer clinical therapy [3]. The understanding of the specific mechanisms of glycolysis regulating ovarian cancer chemoresistance is still limited
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