NEDD4 is involved in acquisition of epithelial-mesenchymal transition in cisplatin-resistant nasopharyngeal carcinoma cells

The neural precursor cell expressed developmentally downregulated protein 4 (NEDD4) plays a pivotal oncogenic role in various types of human cancers. However, the function of NEDD4 in bladder cancer has not been fully investigated. In the present study, we aim to explore whether NEDD4 governs cell proliferation, apoptosis, migration, and invasion in bladder cancer cells. Our results showed that downregulation of NEDD4 suppressed cell proliferation in bladder cancer cells. Moreover, we found that inhibition of NEDD4 significantly induced cell apoptosis. Furthermore, downregulation of NEDD4 retarded cell migration and invasion. Notably, overexpression of NEDD4 enhanced cell growth and inhibited apoptosis. Consistently, upregulation of NEDD4 promoted cell migration and invasion in bladder cancer cells. Mechanically, our Western blotting results revealed that downregulation of NEDD4 activated PTEN and inhibited Notch-1 expression, whereas upregulation of NEDD4 reduced PTEN level and increased Notch-1 level in bladder cancer cells. Our findings indicated that NEDD4 exerts its oncogenic function partly due to regulation of PTEN and Notch-1 in bladder cancer cells. These results further revealed that targeting NEDD4 could be a useful approach for the treatment of bladder cancer.

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“…The PCR reaction was described as previously. 23,36 The expression of GAPDH was used as internal control.…”

Section: Apoptosis Assaymentioning

confidence: 99%

Inhibition of NEDD4 inhibits cell growth and invasion and induces cell apoptosis in bladder cancer cells

Wen

Wang

et al. 2017

Cell Cycle

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“…It is crucial to understand the occurrence of chemoresistance, and eventually how to prevent it for combatting cancer effectively [8,27,28], and it is well known that the ABC transporter family are implicated in multidrug resistance and high-expressed levels of ABCG2 have a greater capacity to expel therapeutic drugs [25,29,30]. Furthermore, accumulating ndings reveal that aberrant Wnt/β-catenin signaling and increased ABCG2 expression are closely correlated to multidrug resistance in many cancers [14,15,31], including NPC [18,17].…”

Section: Discussionmentioning

confidence: 99%

“…Although NPC is generally a good response to radiation therapy, cisplatin-based combinational chemoradiotherapy is required for locally advanced cancers [3,4,5] and the 5-year overall survival rate still remains low [6]. One serious challenge with cisplatin-based chemothrapy is the acquisition of chemoresistance due to increased expressions of ATPbinding cassette (ABC) transporters that is a key mechanism that contributes to multidrug resistance [7,8,9]. Consequently, there is an urgent need for developing new therapeutic agents for circumventing cisplatin resistance in the treatment of NPC.…”

Section: Introductionmentioning

confidence: 99%

Cardamonin Enhances Cisplatin Chemosensitivity of Nasopharyngeal Cancer Cells via Attenuating c-Myc-Mediated β-Catenin/ABCG2 Signaling

Qiao¹,

Li²,

Wu³

et al. 2020

Preprint

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Purpose: Resistance to chemotherapeutic drugs in nasopharyngeal carcinoma(NPC) remains a major obstacle of clinical therapy. To address the issue, screening for natural low-toxicity products as chemosensitizers has become a promising strategy for cancer therapy. In this study, we investigated chemosensitizing effects of cardamonin (CM), a plant-derived chalcone, on cisplatin (DPP)-resistant NPC cells, and explored the molecular mechanism for its antitumor activity. Methods: The chemotherapeutic efficacy of cardamonin, cisplatin and their combination in cisplatin-resistant NPC cells were analyzed using MTT assay, apoptosis assay, and cell cycle analysis. Real-time PCR, western blotting, and cell transfection analysis were performed to assess the synergistic inhibitory action of cardamonin supplemented with cisplatin on Wnt/β-catenin/ABCG2 signaling. The effect of cardamonin on ABCG2 drug efflux function was analyzed by doxorubicin accumulation assay. A CNE2/DPP nude mouse model was used to determine the combinatorial effects of cardamonin on tumor growth in vivo. Results: Cardamonin increased cisplatin-induced cytotoxicity, accompanied by induction of apoptosis and cell cycle arrest in DPP-resistant NPC cells. Moreover, cardamonin could synergized with cisplatin to downregulate β-catenin, c-Myc, and ABCG2. Specifically, cardamonin inhibited Wnt/β-catenin/ABCG2 signaling through c-Myc-mediated transcription inactivation, thereby suppressing the expression of ABCG2 in cisplatin-resistant NPC cells. These findings were confirmed in vivo, wherein cardamonin treatment with cisplatin resulted in reduced tumor growth in a CNE2/DPP xenograft animal model. Conclusions: Taken together, our data firstly demonstrated that cardamonin increased chemosensitivity of nasopharyngeal cancer cells to cisplatin through inactivation of Wnt/β-catenin/ABCG2 signaling, more specifically by inhibition of β-catenin/ABCG2 signaling through c-Myc-mediated transcriptional inactivation, thereby downregulation of ABCG2 and reversal of cisplatin resistance. Thus, in addition to its chemotherapeutic potential, cardamonin may serve as a useful chemosensitizer to conventional chemotherapeutic drugs in the treatment of nasopharyngeal carcinoma.

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“…It is believed that CSC stemness is associated with EMT, and EMT co-exists with chemoresistance, the anti-chemotherapy is merely an intrinsic feature of EMT. EMT association with chemoresistance have been observed in many other cancers such as pancreatic cancer, ovarian cancer, breast cancer, nasopharyngeal cancer and lung cancer [ 44 , 45 , 46 , 47 ]. Our data first showed that NANOGP8 enhances EMT markers and Wnt signals, meanwhile endow the cancer cells with chemoresistance.…”

Section: Discussionmentioning

confidence: 99%

NANOGP8 is the key regulator of stemness, EMT, Wnt pathway, chemoresistance, and other malignant phenotypes in gastric cancer cells

Wang

et al. 2018

PLoS ONE

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BackgroundAccumulating evidence demonstrated that NANOG1, the key transcription factor for embryonic stem cells, is associated with human cancers. NANOGP8, one of the pseudogenes in NANOG gene family, contains an intact open reading frame and also said to be expressed in cancer tissues. Therefore, a systematic study is greatly needed to address the following questions: among NANOG1 and NANOGP8, which gene is the main contributor for NANOG expression in cancer cells and which one is the key regulator responsible for stemness, epithelial-mesenchymal transition (EMT), metastasis, chemoresistance and other malignant phenotypes. Here we try to explore these issues with gastric adenocarcinoma cell lines in vitro using variety of molecular and cellular techniques.MethodsSpecial primers were designed to distinguish PCR products from NANOG1 and NANOGP8. Sphere-forming cells were cultured with serum-free and selective medium. A stable cell line was established with infection of lentivirus containing NANOGP8. qPCR was performed to measure NANOGP8 expression and its association with stemness, EMT and CSC markers in adherent cells and sphere-forming cells. Western blot analysis was deployed to confirm results of the transcript analysis. Experiments of cell proliferation, migration, invasion, clonogenic assay, sphere cell growth assays, cell cycle analysis, β-catenin accumulation and translocation in nucleus, and drug resistance were conducted to measure the impact of NANOGP8 on malignant statuses of gastric cancer cells. Immunofluorescence staining was used to analyze cell subpopulations with different markers.ResultsNANOGP8 is mainly responsible for NANOG expression in sphere-forming (stem cell-like) cells derived from gastric cancer cell lines regardless their differentiation status. Ectopic expression of NANOGP8 significantly up-regulates stemness transcription factors, EMT inducers, and cancer stem cell markers (CSC) including Lgr5. NANOGP8 also promotes expression of the signature genes vimentin and N-caderin for mesenchymal cells and down-regulates the signature gene E-caderin for epithelial cells whereby confer the cells with mesenchymal cell phenotype. In NANOGP8 over-expressed adherent and sphere-forming cells, Lgr5+ cells are significantly increased. Ectopic expression of NANOGP8 endows gastric cells with enhanced proliferation, migration, invasion, sphere-forming and clonogenic capacity, and chemoresistance. NANOGP8 expression also enhances β-catenin accumulation in nucleus and strengthens Wnt signal transduction.ConclusionNANOGP8 is the main regulator of gastric cancer stem cells. It is closely associated with EMT, stemness, and CSC marker as well as Wnt signal pathway. NANOGP8 is correlated with cell proliferation, migration, invasion, clonogenic capacity, β-catenin accumulation in nucleus, and chemoresistance in gastric cancer. NANOGP8 is a promising molecular target for clinical intervention of gastric cancer.

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NEDD4 is involved in acquisition of epithelial-mesenchymal transition in cisplatin-resistant nasopharyngeal carcinoma cells

Cited by 19 publications

References 51 publications

Inhibition of NEDD4 inhibits cell growth and invasion and induces cell apoptosis in bladder cancer cells

Inhibition of NEDD4 inhibits cell growth and invasion and induces cell apoptosis in bladder cancer cells

Cardamonin Enhances Cisplatin Chemosensitivity of Nasopharyngeal Cancer Cells via Attenuating c-Myc-Mediated β-Catenin/ABCG2 Signaling

NANOGP8 is the key regulator of stemness, EMT, Wnt pathway, chemoresistance, and other malignant phenotypes in gastric cancer cells

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