Aurora-A/SOX8/FOXK1 signaling axis promotes chemoresistance via suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells

Sun, Huizhen; Wang, Husheng; Wang, Xue; Aoki, Yoichi; Wang, Xinjing; Yang, Yufei; Cheng, Xi; Wang, Ziliang; Wang, Xipeng

doi:10.7150/thno.43811

Cited by 74 publications

(67 citation statements)

References 52 publications

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“…It is estimated that 70–80% of patients develop chemoresistance following initial surgery and standardized chemotherapy, although through standardized treatment, patients with OC exhibit favorable perioperative efficacy and prognosis. The development of OC chemoresistance is a complex process involving multiple factors, genes and stages, such as BRAF inhibitors and CD44 ( 28 , 29 ), and severely limits the quality of life and prognosis of patients with OC ( 6 , 30 ). The results of the present study revealed that USP46 expression levels were downregulated in OC chemoresistant tissues compared with chemosensitive tissues, suggesting that abnormal expression of USP46 may be crucial for the development of resistance in OC.…”

Section: Discussionmentioning

confidence: 99%

Downregulated expression levels of USP46 promote the resistance of ovarian cancer to cisplatin and are regulated by PUM2

Xu¹,

Zhang²,

Li³

2021

Mol Med Rep

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Ovarian cancer (OC) is a major contributor to cancer-related mortality in women. Despite numerous drugs being available for the treatment and improving the prognosis of OC, resistance to clinical chemotherapy remains a major obstacle for the treatment of advanced OC. Therefore, determining how to reverse the chemoresistance of OC has become a research hotspot in recent years. The present study aimed to reveal the potential mechanism of OC chemoresistance. Reverse transcription-quantitative PCR and western blot analysis were performed to detect the expression levels of Ubiquitin-specific peptidase 46 (USP46) and Pumilio 2 (PUM2) in OC. Cell viability and apoptosis were evaluated by Cell Counting Kit-8 assay and flow cytometry, respectively. The association between USP46 and PUM2 was assessed by RNA immunoprecipitation. The results of the present study revealed that the expression levels of USP46 which is associated with tumor progression, was downregulated, while PUM2 expression levels were upregulated in cisplatin (DDP)-resistant OC cells and patient tissues. The downregulation of USP46 expression levels in SKOV3 cells significantly inhibited cell apoptosis and increased cell viability. In SKOV3/DDP cells, the upregulation of USP46 expression levels notably suppressed cell viability and increased cell apoptosis. The results of the RNA immunoprecipitation chip assay demonstrated that PUM2 bound to USP46 and regulated its expression. Furthermore, following the knockdown of USP46 expression, the mRNA and protein expression levels of the cell apoptosis-related protein, Bcl-2, were upregulated, whereas the expression levels of caspase-3, caspase-9 and Bax were significantly downregulated. In addition, phosphorylated AKT expression levels were notably upregulated. Following the overexpression of USP46 in SKOV3/DDP cells, the opposite trends were observed. In SKOV3 cells, the knockdown of PUM2 could reverse the DDP resistance induced by small interfering RNA-USP46 as the expression levels of Bcl-2 were downregulated whereas those of caspase-3, caspase-9 and Bax were upregulated compared with the small interfering-USP46 group. Similarly, in SKOV3/DDP cells, the overexpression of PUM2 could reverse DDP sensitivity induced by the overexpression of USP46. In conclusion, the findings of the present study suggested that the downregulation of USP46 expression levels may promote DDP resistance in OC, which may be regulated by PUM2. Therefore, targeting PUM2/USP46 may be an effective way to reverse DDP resistance in OC.

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Section: Discussionmentioning

confidence: 99%

Downregulated expression levels of USP46 promote the resistance of ovarian cancer to cisplatin and are regulated by PUM2

Xu¹,

Zhang²,

Li³

2021

Mol Med Rep

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“…Compared to the classical 2D cancer cell lines, organoids are more difficult to operate and more expensive to maintain. However, they represent more reliably the pathological features of the tumor, as PDOs maintain genetic stability and tumor heterogeneity [6,[8][9][10][67][68][69][70][71][72][73][74], which instead are lost during the long-term selection required to establish 2D tumor cell lines. In comparison with patient-derived xenografts (PDXs) or genetically engineered animal models, PDOs are less time consuming, less expensive and more appropriate for high-throughput drug screening.…”

Section: Patient-derived Organoidsmentioning

confidence: 99%

“…In comparison with patient-derived xenografts (PDXs) or genetically engineered animal models, PDOs are less time consuming, less expensive and more appropriate for high-throughput drug screening. Furthermore, PDOs are usually obtained with higher success rate than PDXs and can also be formed from non-transformed cell cultures or preinvasive cancer models [6,[8][9][10][67][68][69][70][71][72][73][74]. Lastly, with respect to spheroids, which are clusters of proliferating cells that assemble in 3D sphere-like structures floating in the culture medium [75], PDOs offer a better representation of the architecture of the tumor, as they assemble onto a reconstituted matrix that resembles the basal lamina of epithelia and recapitulate the cellular heterogeneity of the tumor mass.…”

Section: Patient-derived Organoidsmentioning

confidence: 99%

“…Lastly, with respect to spheroids, which are clusters of proliferating cells that assemble in 3D sphere-like structures floating in the culture medium [75], PDOs offer a better representation of the architecture of the tumor, as they assemble onto a reconstituted matrix that resembles the basal lamina of epithelia and recapitulate the cellular heterogeneity of the tumor mass. Nevertheless, one limitation of PDOs is currently represented by the lack of reliable protocols capable to faithfully reproduce the tumor microenvironment, which comprises the stroma, immune cells and blood vessels [6,[8][9][10][67][68][69][70][71][72][73][74]. However, the recent development of organoids cocultured with tumor microenvironment components holds promise for the possibility to evaluate complex features of tumors in the near future [76,77].…”

Section: Patient-derived Organoidsmentioning

confidence: 99%

“…Several protocols to obtain PDO cultures from OC have been reported in the past three years [6,[8][9][10][67][68][69][70][71][72][73][74]. The main experimental conditions and key findings of these studies are summarized in Table 1.…”

Section: Ovarian Cancer Pdosmentioning

confidence: 99%

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Patient-derived organoids and high grade serous ovarian cancer: from disease modeling to personalized medicine

Nero

Vizzielli

Lorusso

et al. 2021

J Exp Clin Cancer Res

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Background High grade serous ovarian cancer (HGSOC) is among the deadliest human cancers and its prognosis remains extremely poor. Tumor heterogeneity and rapid acquisition of resistance to conventional chemotherapeutic approaches strongly contribute to poor outcome of patients. The clinical landscape of HGSOC has been radically transformed since the advent of targeted therapies in the last decade. Nevertheless, the lack of predictive biomarkers informing on the differential clinical benefit in select subgroups, and allowing patient-centric approaches, currently limits the efficacy of these novel therapies. Thus, rational selection of the best possible treatment for each patient represents a clinical priority in order to improve outcome, while limiting undesirable effects. Main body In this review, we describe the state of the art and the unmet needs in HGSOC management, illustrate the treatment options that are available and the biomarkers that are currently employed to orient clinical decisions. We also describe the ongoing clinical trials that are testing new therapeutic approaches for HGSOC. Next, we introduce the organoid technology as a promising, expanding strategy to study cancer and to develop personalized therapeutic approaches. In particular, we discuss recent studies that have characterized the translational potential of Patient’s Derived Organoids (PDOs) to inform on drug sensitivity of HGSOC patients. Conclusions PDOs can predict the response of patients to treatments and may therefore guide therapeutic decisions. Although preliminary results appear encouraging, organoids still need to be generated and expanded efficiently to enable drug screening in a clinically meaningful time window. A new generation of clinical trials based on the organoid technology should guarantee tailored approaches to ovarian cancer management, as it is now clear that the one-size-fits-all approach cannot lead to efficient and meaningful therapeutic advancements.

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The Fibrillin‐1/VEGFR2/STAT2 signaling axis promotes chemoresistance via modulating glycolysis and angiogenesis in ovarian cancer organoids and cells

Wang

Chen

Zuo

et al. 2022

Cancer Communications

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Background Chemotherapy resistance is a primary reason of ovarian cancer therapy failure; hence it is important to investigate the underlying mechanisms of chemotherapy resistance and develop novel potential therapeutic targets. Methods RNA sequencing of cisplatin‐resistant and ‐sensitive (chemoresistant and chemosensitive, respectively) ovarian cancer organoids was performed, followed by detection of the expression level of fibrillin‐1 (FBN1) in organoids and clinical specimens of ovarian cancer. Subsequently, glucose metabolism, angiogenesis, and chemosensitivity were analyzed in structural glycoprotein FBN1‐knockout cisplatin‐resistant ovarian cancer organoids and cell lines. To gain insights into the specific functions and mechanisms of action of FBN1 in ovarian cancer, immunoprecipitation, silver nitrate staining, mass spectrometry, immunofluorescence, Western blotting, and Fӧrster resonance energy transfer‐fluorescence lifetime imaging analyses were performed, followed by in vivo assays using vertebrate model systems of nude mice and zebrafish. Results FBN1 expression was significantly enhanced in cisplatin‐resistant ovarian cancer organoids and tissues, indicating that FBN1 might be a key factor in chemoresistance of ovarian cancer. We also discovered that FBN1 sustained the energy stress and induced angiogenesis in vitro and in vivo, which promoted the cisplatin‐resistance of ovarian cancer. Knockout of FBN1 combined with treatment of the antiangiogenic drug apatinib improved the cisplatin‐sensitivity of ovarian cancer cells. Mechanistically, FBN1 mediated the phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) at the Tyr1054 residue, which activated its downstream focal adhesion kinase (FAK)/protein kinase B (PKB or AKT) pathway, induced the phosphorylation of signal transducer and activator of transcription 2 (STAT2) at the tyrosine residue 690 (Tyr690), promoted the nuclear translocation of STAT2, and ultimately altered the expression of genes associated with STAT2‐mediated angiogenesis and glycolysis. Conclusions The FBN1/VEGFR2/STAT2 signaling axis may induce chemoresistance of ovarian cancer cells by participating in the process of glycolysis and angiogenesis. The present study suggested a novel FBN1‐targeted therapy and/or combination of FBN1 inhibition and antiangiogenic drug for treating ovarian cancer.

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Aurora-A/SOX8/FOXK1 signaling axis promotes chemoresistance via suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells

Cited by 74 publications

References 52 publications

Downregulated expression levels of USP46 promote the resistance of ovarian cancer to cisplatin and are regulated by PUM2

Downregulated expression levels of USP46 promote the resistance of ovarian cancer to cisplatin and are regulated by PUM2

Patient-derived organoids and high grade serous ovarian cancer: from disease modeling to personalized medicine

The Fibrillin‐1/VEGFR2/STAT2 signaling axis promotes chemoresistance via modulating glycolysis and angiogenesis in ovarian cancer organoids and cells

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