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Inhibition of ZIP4 reverses epithelial-to-mesenchymal transition and enhances the radiosensitivity in human nasopharyngeal carcinoma cells.

ABSTRACT: ZIP4 is a zinc transporter involved in epithelial cell morphology and migration in various cancers. In the epithelial-to-mesenchymal transition (EMT), epithelial cells transition into mesenchymal cells. The EMT plays a crucial role in invasiveness and metastasis during tumorigenesis. The aim of this study was to investigate the role of ZIP4 in the invasiveness and radiosensitivity of human nasopharyngeal carcinoma (NPC). In this study, results from 99 human patients with NPC showed that ZIP4 expression levels significantly correlated with a higher TN (tumor, lymph node) classification, as well as shorter overall survival (OS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS). Forced overexpression of ZIP4 promoted the migration and invasion of C666-1 cells through regulation of the EMT process. In contrast, ZIP4 silencing by lentivirus-mediated shRNA inhibited the EMT and metastasis of C666-1 cells in vitro and in vivo. Importantly, protein microarray analyses showed that downregulation of ZIP4 in C666-1 cells resulted in the decreased abundance of phosphoinositide 3-kinase (PI3K) p85 (Tyr607), phosphorylated (p)-Akt (Ser473), phosphorylated (p)-Akt (Thr308), and phosphorylated glycogen synthase kinase 3? (pGSK3?; Ser9). These data suggest that ZIP4 induces the EMT and promotes migration and invasion via the PI3K/Akt signaling pathway in NPC. Moreover, ZIP4 silencing significantly enhanced radiation-induced apoptosis and growth inhibition of human C666-1 cells in vitro and enhanced the antitumor activity of ionizing radiation (IR), leading to tumor growth inhibition in vivo. These results demonstrate that ZIP4 is a novel prognostic factor for malignant NPC progression. More importantly, targeting ZIP4, along with radiotherapy, may be an effective new treatment for NPC.

SUBMITTER: Zeng Q

PROVIDER: S-EPMC6683154 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Inhibition of ZIP4 reverses epithelial-to-mesenchymal transition and enhances the radiosensitivity in human nasopharyngeal carcinoma cells.

Zeng Qi Q Liu Yi-Min YM Liu Jun J Han Jian J Guo Jian-Xin JX Lu Shun S Huang Xue-Mei XM Yi Ping P Lang Jin-Yi JY Zhang Peng P Wang Chun-Ting CT

Cell death & disease 20190805 8

ZIP4 is a zinc transporter involved in epithelial cell morphology and migration in various cancers. In the epithelial-to-mesenchymal transition (EMT), epithelial cells transition into mesenchymal cells. The EMT plays a crucial role in invasiveness and metastasis during tumorigenesis. The aim of this study was to investigate the role of ZIP4 in the invasiveness and radiosensitivity of human nasopharyngeal carcinoma (NPC). In this study, results from 99 human patients with NPC showed that ZIP4 exp ...[more]

PMID: 31383854

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Project description:BackgroundRecurrence due to the development of radioresistance remains a major challenge in the clinical management of nasopharyngeal carcinoma. The objective of this study was to increase the sensitivity of nasopharyngeal carcinoma cells to ionizing radiation by enhancing oxidative stress and ferroptosis caused by disrupting the mitochondrial anti-oxidant enzyme system.MethodsOxidative stress cell model was constructed by SOD2 knockdown using shRNA. The expression and activity of DHODH was suppressed by siRNA and brequinar in SOD2 depleted cells. Protein levels were determined by western blotting and ferroptosis was assessed by C11 BODIPY and malondialdehyde assay. Cell viability was evaluated using CCK-8 assay while radiotoxicity was assessed by colony formation assay. Cellular ATP level was determined by ATP assay kits, ROS was determined by DCFD and DHE, while mitochondrial oxygen consumption was determined by seahorse assay. Data were analyzed by two-tailed independent t-test.ResultsRadiation upregulated SOD2 expression and SOD2 depletion increased cellular O2.-, malondialdehyde, and the fluorescence intensity of oxidized C11 BODIPY. It also resulted in mitochondrial damage. Its depletion decreased colony formation both under ionizing and non-ionizing radiation conditions. The ferroptosis inhibitor, deferoxamine, rescued cell viability and colony formation in SOD2 depleted cells. Cellular level of malondialdehyde, fluorescence intensity of oxidized C11 BODIPY, O2.- level, ATP, and mitochondrial oxygen consumption decreased following DHODH inhibition in SOD2 depleted cells. Cell viability and colony formation was rescued by DHODH inhibition in SOD2 depleted cells.ConclusionInducing oxidative stress by SOD2 inhibition sensitized nasopharyngeal carcinoma cells to ionizing radiation via ferroptosis induction. This was found to be dependent on DHODH activity. This suggests that DHODH inhibitors should be used with caution during radiotherapy in nasopharyngeal carcinoma patients.

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Inhibition of ZIP4 reverses epithelial-to-mesenchymal transition and enhances the radiosensitivity in human nasopharyngeal carcinoma cells.

Publications

Inhibition of ZIP4 reverses epithelial-to-mesenchymal transition and enhances the radiosensitivity in human nasopharyngeal carcinoma cells.

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