Dysregulated BARD1 Contributes to Paclitaxel Resistance in Ovarian Cancer via Up-regulating CYP2C8.

Introduction: Frontline treatment regimens for ovarian cancer routinely consist of repeated cycles of paclitaxel/platinum doublets; however, chemotherapy resistance frequently leads to recurrent or refractory disease. Novel therapeutic strategies aimed at circumventing or preventing resistance are needed for improved disease control. Experimental Procedures: Multiple paclitaxel-resistant ovarian cancer cell line models were established via repeated cycles of paclitaxel treatment in vitro. Resistance to paclitaxel was assessed using dose response cell viability assays with CellTiter-Glo 2.0 and calculation of IC50 values using a 4-parameter logistic regression model. RNAseq and whole-exome sequencing were used to examine genomic variation distinguishing resistant lines from their sensitive counterparts. Recurrent expression differences associated with paclitaxel resistance were identified, a subset of which were selected for further validation. Candidate genes and pathways associated with paclitaxel resistance were manipulated using siRNA and/or small-molecule inhibitors and assessed for the ability to alter the resistant phenotype. Synergistic interactions for drug combinations were evaluated using the Loewe Additivity model. Results: Paclitaxel-resistant ovarian cancer cell lines were derived from TOV-21G, OVCAR-3, and UWB1.289 cells. Resistant cell lines exhibited increases in paclitaxel IC50 ranging from 6.5 to 94-fold over their parental control cells. RNAseq analysis identified the transcript encoding P-glycoprotein (P-gp), ABCB1, among the most highly upregulated genes in the resistant TOV-21G and OVCAR-3 cells while no such induction of expression was seen in resistant UWB1.289 cells. Previous reports have shown several different tyrosine kinase inhibitors (e.g., lapatinib, neratinib, dasatinib, etc.) have the ability to inhibit P-gp function. We tested a panel of tyrosine kinase inhibitors for the ability to sensitize resistant P-gp-overexpressing ovarian cancer cells to paclitaxel. The most potent synergistic antiproliferative activity was observed when lapatinib was combined with paclitaxel treatment of resistant TOV-21G and OVCAR-3 cells; however, a similar interaction was not observed in resistant UWB1.289 cells that do not overexpress P-gp. The dependence of this synergistic effect on P-gp expression was confirmed by using siRNA to inhibit P-gp expression in paclitaxel-resistant TOV-21G and OVCAR-3 cells, significantly reducing paclitaxel IC50 by 20.7 and 6.2-fold, respectively, and eliminating cytotoxic synergy. Conclusions: Paclitaxel and lapatinib have synergistic anticancer properties when used to treat P-gp-overexpressing ovarian cancer cells. The addition of lapatinib to second-line dose-dense paclitaxel therapy could be an effective strategy for a subset of ovarian cancer patients with recurrent disease and warrants further clinical exploration. Citation Format: Rob McCorkle, Justin W. Gorski, Abigail Anderson, Jill M. Kolesar. Lapatinib potentiates the antitumor effects of paclitaxel treatment in resistant ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A50.

Regulators of Mitotic Arrest and Ceramide Metabolism Are Determinants of Sensitivity to Paclitaxel and Other Chemotherapeutic Drugs

Targeting Gonadotropin-releasing Hormone Receptor Inhibits the Early Step of Ovarian Cancer Metastasis by Modulating Tumor-mesothelial Adhesion

Epithelial ovarian cancer is the fourth most common cause of cancer death among women in the developed world. Currently only 30% of ovarian cancer patients remain free from disease long term. Paclitaxel is an integral component of primary therapy for ovarian cancer, but less than half of ovarian cancers respond to the drug. Enhancing the response to primary therapy with paclitaxel could improve outcomes for women with the disease. In recent years, we have identified several kinases that regulate the sensitivity of cancer cells to paclitaxel by modulating cancer metabolism, enhancing microtubule stability, inhibiting centrosome splitting or blocking AKT/survivin signaling. We performed siRNA kinome-screens to identify molecular targets whose decreased expression overcomes paclitaxel resistance and increases paclitaxel sensitivity in ovarian cancer cells. Upon assessing cell viability, we showed that 20% of the potential kinase targets whose knockdown modulates paclitaxel sensitivity participate in glucose and energy metabolism. Among these, a leading candidate was 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2), an isoform of the glycolytic enzyme phosphofructokinase (PFK2). Many cancer cells depend on glucose for survival. Glycolysis involves ten metabolic reactions catalyzed by enzymes whose expression is frequently increased during malignant transformation. Many reports document the role of oncogenic signaling in regulating the activity of metabolic enzymes to support the enhanced macromolecule synthesis required for rapid proliferation of cancer cells. Cancer cells express altered levels of the different PFK-2/FBPase-2 isoenzymes and even modulate their relative kinase and bisphosphatase activities according to metabolic needs in a spatial and/or temporal manner. PFKFB2 is a bifunctional glycolytic enzyme that regulates the level of fructose-2,6-bisphosphate (Fru-2,6-BP) and is overexpressed in a fraction of ovarian and breast cancers. We found that knockdown of PFKFB2 inhibited clonogenic growth and enhanced paclitaxel sensitivity in ovarian and breast cancer cell lines with wild-type TP53 (wtTP553). Additionally, PFKFB2 siRNA or PFKFB2 shRNA significantly inhibited tumor growth and enhanced sensitivity to paclitaxel in xenografts derived from two ovarian cancer cell lines. Knockdown of PFKFB2 increased the rate of glycolysis, but decreased the flow of intermediates through the pentose-phosphate pathway in cancer cell lines with wtTP53, decreasing NADPH. Reactive oxygen species (ROS) accumulated after PFKFB2 knockdown, which stimulated phosphorylation of Janus kinase (JNK), induced G1 cell cycle arrest, and initiated apoptosis that depended upon upregulation of p21Cip1 and Puma. Thus, PFKFB2 is a glycolytic enzyme that drives tumor cell growth and enhances paclitaxel resistance by inhibiting TP53-dependent G1 cell cycle arrest and apoptosis. These findings highlight the interaction of cancer-altered metabolism with cell proliferation and chemosensitivity, which may provide a novel target in patients with ovarian and breast cancers where TP53 function remains intact. We also found that knockdown of kinases that regulate microtubule stability could sensitize ovarian cancer cells to paclitaxel treatment. In previous studies, baseline microtubule stability correlated with response to paclitaxel in ovarian cancer cell lines and both parameters could be enhanced by knockdown of individual kinases. Using the initial 14 kinase targets, we performed assays of microtubule stability, apoptosis, and cell cycle arrest with all possible pairs of kinase siRNA which enhance paclitaxel sensitivity across multiple cell lines and found that dual knockdown of IKBKB/STK39 had the greatest effect on enhancing paclitaxel stability. Our study documents the impact of sequentially silencing IKBKB and STK39 on paclitaxel sensitivity, providing a rationale for siRNA-based therapy. Different siRNAs are in the developmental pipeline for a variety of diseases including cancer, and more than a dozen are in phase I or II clinical trials. One of the most promising candidates to emerge from our kinase screen was salt inducible kinase 2 (SIK2), a serine/threonine kinase that is required for bipolar mitotic spindle formation and normal mitotic progression. With Dr. Ahmed Ahmed, we previously found knockdown of SIK2 induces polyploidy by blocking centrosome splitting and inhibits PI3K, sensitizing cells to paclitaxel. We demonstrated that knockdown of SIK2 inhibits xenograft growth and potentiates paclitaxel activity in vivo. Subsequently, we have partnered with Arrien Pharmaceuticals to test a small-molecule inhibitor of SIK2. We have found that novel SIK2 inhibitors, ARN-3236 and ARN3261, block the activity of SIK2 kinase and inhibit ovarian cancer cell growth, enhancing paclitaxel sensitivity in cultured cells and in xenografts. ARN-3261 will enter first-in-human trials at MD Anderson early next year. Taken together, our results support the development of small-molecule kinase inhibitors that modulate glycolysis, enhance microtubule stability, induce polyploidy, and inhibit AKT/survivin signaling, providing novel routes to enhance primary paclitaxel-based therapy for ovarian cancer and to improve patient outcomes. Citation Format: Zhen Lu. Kinase-mediated modulation of paclitaxel sensitivity in ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA08.

BackgroundThe metzincin family of metalloproteinases and the tissue inhibitors of metalloproteinases (TIMPs) are essential proteins required for biological processes during cancer progression. This study aimed to determine the role of TIMP-2 in ovarian cancer progression and chemoresistance by reducing TIMP-2 expression in vitro in Fallopian tube secretory epithelial (FT282) and ovarian cancer (JHOS2 and OVCAR4) cell lines.MethodsFT282, JHOS2 and OVCAR4 cells were transiently transfected with either single or pooled TIMP-2 siRNAs. The expression of different genes after TIMP-2 knock down (T2-KD) or in response to chemotherapy was determined at the mRNA level by quantitative real time PCR (qRT-PCR) and at the protein level by immunofluorescence. Sensitivity of the cell lines in response to chemotherapy after TIMP-2 knock down was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5-Ethynyl-2′-deoxyuridine (EdU) assays. Cell invasion in response to TIMP-2 knockdown was determined by xCELLigence.ResultsSixty to 90 % knock down of TIMP-2 expression was confirmed in FT282, OVCAR4 and JHOS2 cell lines at the mRNA and protein levels. TIMP-2 knock down did not change the mRNA expression of TIMP-1 or TIMP-3. However, a significant downregulation of MMP-2 in T2-KD cells occurred at both the protein and activation levels, compared to Control (Cont; scrambled siRNA) and Parental cells (P, transfection reagent only). In contrast, membrane bound MT1-MMP protein levels were significantly upregulated in T2-KD compared to Cont and P cells. T2-KD cells exhibited enhanced proliferation and increased sensitivity to cisplatin and paclitaxel treatments. Enhanced invasion was observed in the T2-KD-JOSH2 and OVCAR4 cells but not in T2-KD-FT282 cells. Treatment with cisplatin or paclitaxel significantly elevated the expression of TIMP-2 in Cont cells but not in T2-KD cells, consistent with significantly elevated expression of chemoresistance and CSC markers and activation of STAT3. Furthermore, a potent inhibitor of STAT3 activation, Momelotinib, suppressed chemotherapy-induced activation of P-STAT3 in OVCAR4 cells with concomitant reductions in the expression of chemoresistance genes and CSC markers.ConclusionsThe above results suggest that TIMP-2 may have a novel role in ovarian cancer proliferation, invasion and chemoresistance.

Background: Drug resistance is a major obstacle in chemotherapy for ovarian cancer, wherein the up regulation of drug-resistant genes plays an important role. The cytoplasmic polyadenylation element binding protein 4 (CPEB4) is an RNA binding protein that controls mRNA cytoplasmic polyadenylation and translation. Methods: The expression of CPEB4 in paclitaxel-resistant ovarian cancer cell lines and recurrent ovarian tumors relative to counterparts was determined by qRT-PCR, Western blotting and immunohistochemistry. The response to paclitaxel treatment was evaluated by cellular viability test and colony formation assay. RNA immunoprecipitation and poly(A) tail test were applied to examine the levels of RNA binding and cytoplasmic polyadenylation. Results: CPEB4 is elevated in paclitaxel-resistant ovarian cancer cells and recurrent ovarian tumors treated with paclitaxel-based chemotherapy. In addition, CPEB4 overexpression promotes paclitaxel resistance in ovarian cancer cells in vitro, and vice versa, CPEB4 knockdown restores paclitaxel sensitivity, indicating that CPEB4 confers paclitaxel resistance in ovarian cancer cells. Mechanistically, CPEB4 binds with the taxol (paclitaxel)-resistance-associated gene-3 (TRAG-3/CSAG2) mRNAs and induces its expression at a translational level. Moreover, CSAG2 expression is upregulated in paclitaxel-resistant ovarian carcinoma and cancer cell lines, and more importantly, siRNA-mediated CSAG2 knockdown overtly attenuates CPEB4-mediated paclitaxel resistance. Conclusion: This study suggests that the drug-resistant protein CSAG2 is translationally induced by CPEB4, which underlies CPEB4-promoted paclitaxel resistance in ovarian cancer in vitro. Thus, interfering CPEB4/CSAG2 axis might be of benefit to overcome paclitaxel-resistant ovarian cancer.

BackgroundChemoresistance is one of the major obstacles for cancer therapy in the clinic. Nuclear paraspeckle assembly transcript 1 (NEAT1) has been reported as an oncogene in most malignancies such as lung cancer, esophageal cancer, and gastric cancer. This study is designed to investigate the function of NEAT1 in paclitaxel (PTX) resistance of ovarian cancer and its potential molecular mechanism.Patients and methodsThe expressions of NEAT1 and miR-194 in ovarian cancer tissues and cells were estimated by quantitative real-time polymerase chain reaction (qRT-PCR). MTT, flow cytometry, and Western blot assays were used to assess the effect of NEAT1 on PTX resistance in PTX-resistant ovarian cancer cells. Luciferase reporter assay was applied to examine the association between NEAT1, zinc finger E-box-binding homeobox 1 (ZEB1) and miR-194. Xenograft tumor model was established to confirm the biological role of NEAT1 in PTX resistance of ovarian cancer in vivo.ResultsNEAT1 was upregulated, and miR-194 was downregulated in PTX-resistant ovarian cancer tissues and cells. Functionally, NEAT1 knockdown enhanced cell sensitivity to PTX via promoting PTX-induced apoptosis in vitro. NEAT1 was identified as a molecular sponge of miR-194 to upregulate ZEB1 expression. Mechanistically, NEAT1-knockdown-induced PTX sensitivity was mediated by miR-194/ZEB1 axis. Moreover, NEAT1 knockdown improved PTX sensitivity of ovarian cancer in vivo.ConclusionNEAT1 contributed to PTX resistance of ovarian cancer cells at least partly through upregulating ZEB1 expression by sponging miR-194, elucidating a novel regulatory pathway of chemoresistance in PTX-resistant ovarian cancer cells and providing a possible long noncoding RNA (lncRNA)-targeted therapy for ovarian cancer.

RSK4 confers paclitaxel resistance to ovarian cancer cells, which is resensitized by its inhibitor BI-D1870

Purpose: Ovarian cancer is the most lethal gynecologic malignancy. Platinum-paclitaxel combination chemotherapy is the current standard postoperative care for patients with advanced ovarian cancer. Despite developments in current chemotherapy regimens in the last decades, overall 5-year survival rate for patients with advanced disease remains approximately 30%, mainly due to primary or acquired drug resistance. Therefore, overcoming chemoresistance remains the great challenge in ovarian cancer management. However, mechanisms underlying chemoresistance to paclitaxel have not been fully understood. The aim of this study is to identify key miRNAs which regulate paclitaxel resistance in ovarian cancer and to pursue those potential as therapeutic targets. Methods: Using two serous ovarian cancer cell lines, SKVO3ip1 and HeyA8, paclitaxel resistant ovarian cancer cell lines were established by a continuous exposure of paclitaxel. MiRNA PCR arrays were performed and miR-194 was found to be one of down-regulated miRNAs in paclitaxel-resistant cell lines. The effect of miR-194 on paclitaxel resistance was assessed by transducing the precursor miRNA into ovarian cancer cells. In silico analysis revealed MDM-2 is one possible putative target of miR-194 and it was assessed using luciferase reporter assay. Since MDM-2 is one of key regulator of P53 ubiquitination, the effect of miR-194 on cell cycle in ovarian cancer cell was assessed. To analyze the impact of miR-194 and MDM-2 expression on patient survival, Kaplan-Meier and log-rank methods were used using The Cancer Genome Atlas (TCGA) dataset. Results: While IC50 values of SKOV3ip1 and HeyA8 were 5.0 nM and 3.5 nM respectively, those of paclitaxel resistant cell lines, named as SKOV3ip1-TR and HeyA8-TR, were both over 300 nM. In both resistant cell lines, miR-194 was found to be down-regulated compared with their parental cell lines. Up-regulation of miR-194 sensitized resistant cells to paclitaxel. Conversely, its downregulation induced paclitaxel resistance in parental cells. Luciferase reporter assay revealed that miR-194 directly suppressed MDM-2 transcriptional activity. In resistant cell lines, MDM-2 was up-regulated compared with their parental cell lines. MiR-194 induced P21 upregulation and G1 phase arrest in resistant cell lines through the downregulation of MDM-2. In TCGA dataset, high MDM-2 expression was associated with shorter progression-free survival of ovarian cancer patients (concrete data, p=0.046). Conclusion: miR-194 acts as a tumor suppressor miRNA through the sensitization to paclitaxel and can be considered as a therapeutic option to overcome paclitaxel-resistant in ovarian cancer patients. Citation Format: Koji Nakamura, Kenjiro Sawada, Akihiko Yoshimura, Erica Nakatsuka, Yasuto Kinose, Seiji Mabuchi, Tadashi Kimura. MiR-194 modulates paclitaxel resistance in ovarian cancer cells through the regulation of MDM-2 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3436. doi:10.1158/1538-7445.AM2017-3436

Although ovarian cancer usually responds well to platinum- and taxane-based first-line chemotherapy, most patients develop recurrence and chemoresistance. Regenerating gene 4 (REG4) is a secretory protein involved in cell differentiation and proliferation. We found higher REG4 expression in ovarian cancer than in normal tissues (p < .05). Regenerating gene 4 expression was negatively associated with overall, progression-free or post-progression survival rates of patients with ovarian cancer receiving platinum or paclitaxel treatment (p < .05) according to a Kaplan–Meier plotter. Regenerating gene 4 overexpression resulted in either cisplatin or paclitaxel resistance, and apoptosis resistance in CAOV3 ovarian cancer cells (p < .05). REG4-transfected ovarian cancer cells showed stronger migration and invasion treated with cisplatin or paclitaxel (p < .05). Additionally, cisplatin or paclitaxel exposure led to the overexpression of phosphorylated phosphoinositide 3-kinase (p-PI3K), p-Akt, phosphorylated mammalian target of rapamycin (p-mTOR), glutathione S-transferase-π, survivin, and B-cell lymphoma 2 in REG4 transfectants compared with control cells (p < .05). These findings suggested that REG4 expression was up-regulated in ovarian cancer, and associated with poor survival and chemotherapy resistance. REG4 promoted the occurrence, development, and chemotherapy resistance of ovarian cancer by regulating cell proliferation, apoptosis, migration, and invasion, and PI3K/Akt/m-TOR signalling pathways. IMPACT STATEMENT What is already known on this subject? REG4 mRNA expression is up-regulated in many digestive cancers. High REG4 expression was associated with an adverse prognosis, high tumour and nodal stages, poor differentiation, and hepatic and peritoneal metastases of digestive cancers. REG4 expression conferred cancer cells with increased resistance to chemoradiotherapy, especially 5-FU-based treatment, by activating the MAPK/Erk/Bim signalling pathway. What do the results of this study add? REG4 was highly expressed in ovarian cancer. The expression of p-PI3K, p-AKT, p-mTOR, GST-π, survivin, and Bcl-2 was increased in REG4-overexpressing cells. High REG4 expression was significantly associated with inferior OS, PFS, and PPS rates in patients with ovarian cancer receiving platinum chemotherapy. REG4 mediated cisplatin and paclitaxel resistance in CAOV3 ovarian cancer cells. The percentage of apoptotic cells was markedly lower in REG4-transfected compared to mock-transfected cells after cisplatin or paclitaxel treatment. What are the implications of these findings for clinical practice and/or further research? This study aimed to evaluate the prognostic significance of REG4 expression in ovarian cancer treated with platinum and paclitaxel, to explore REG4 chemoresistance mechanisms to platinum and paclitaxel, and to provide a scientific experimental basis for the clinical treatment and outcome evaluation of ovarian cancer. In order to provide comprehensive clinical treatment of ovarian cancer, it is helpful to improve our understanding of multi-drug resistance and identify new cancer diagnostic biomarkers.

CCL2 overexpression is associated with paclitaxel resistance in ovarian cancer cells via autocrine signaling and macrophage recruitment

&lt;div&gt;Abstract&lt;p&gt;Ovarian cancer is a common malignant tumor in the female reproductive system. Paclitaxel resistance is the primary cause of treatment failure in patients with ovarian cancer. Therefore, elucidating the mechanisms by which ovarian cancer develops paclitaxel resistance is crucial for achieving better therapeutic outcomes. This study analyzed data from the GSE50831 dataset (the response of 21 ovarian cancer cell lines to paclitaxel), the GSE26193 dataset (the progression of 107 patients with ovarian cancer), and the Ovarian Cancer Genome Atlas. Key differentially expressed genes were selected through intersection analysis, least absolute shrinkage and selection operator, and multivariate Cox regression analysis. Experiments were conducted to validate the candidate gene, &lt;i&gt;NOC2L&lt;/i&gt;, and explore its role in the development of paclitaxel resistance in ovarian cancer cells. Data from these datasets showed that NOC2L was upregulated in all ovarian cancer cell lines after paclitaxel treatment, and this upregulation was associated with poorer patient progression. Both loss- and gain-of-function experiments confirmed that NOC2L promotes ovarian cancer cell resistance to paclitaxel. The Ovarian Cancer Genome Atlas dataset showed that NOC2L is negatively correlated with the NADH:ubiquinone oxidoreductase core subunit family (NDUF) proteins: NDUFB4, NDUFA1, NDUFS4, NDUFB1, NDUFA2, NDUFA4, and MT-ND3. Studies have revealed that NOC2L decreases the expression of NDUF proteins, particularly NDUFA4, by suppressing histone acetylation, resulting in a remodeling of energy metabolism toward aerobic glycolysis. Collectively, NOC2L inducing energy metabolism to aerobic glycolysis is a consistent mechanism in various ovarian cancer cells resistant to paclitaxel. Hence, NOC2L is a promising target to improve the sensitivity of ovarian cancer cells to paclitaxel.&lt;/p&gt;&lt;/div&gt;

Ovarian cancer is a common malignant tumor in the female reproductive system. Paclitaxel resistance is the primary cause of treatment failure in patients with ovarian cancer. Therefore, elucidating the mechanisms by which ovarian cancer develops paclitaxel resistance is crucial for achieving better therapeutic outcomes. This study analyzed data from the GSE50831 dataset (the response of 21 ovarian cancer cell lines to paclitaxel), the GSE26193 dataset (the progression of 107 patients with ovarian cancer), and the Ovarian Cancer Genome Atlas. Key differentially expressed genes were selected through intersection analysis, least absolute shrinkage and selection operator, and multivariate Cox regression analysis. Experiments were conducted to validate the candidate gene, NOC2L, and explore its role in the development of paclitaxel resistance in ovarian cancer cells. Data from these datasets showed that NOC2L was upregulated in all ovarian cancer cell lines after paclitaxel treatment, and this upregulation was associated with poorer patient progression. Both loss- and gain-of-function experiments confirmed that NOC2L promotes ovarian cancer cell resistance to paclitaxel. The Ovarian Cancer Genome Atlas dataset showed that NOC2L is negatively correlated with the NADH:ubiquinone oxidoreductase core subunit family (NDUF) proteins: NDUFB4, NDUFA1, NDUFS4, NDUFB1, NDUFA2, NDUFA4, and MT-ND3. Studies have revealed that NOC2L decreases the expression of NDUF proteins, particularly NDUFA4, by suppressing histone acetylation, resulting in a remodeling of energy metabolism toward aerobic glycolysis. Collectively, NOC2L inducing energy metabolism to aerobic glycolysis is a consistent mechanism in various ovarian cancer cells resistant to paclitaxel. Hence, NOC2L is a promising target to improve the sensitivity of ovarian cancer cells to paclitaxel.

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.

Chemotherapy