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JNK pathway inhibition enhances chemotherapeutic sensitivity to Adriamycin in nasopharyngeal carcinoma cells.

ABSTRACT: The role of c-Jun N-terminal kinases (JNKs) in the pathogenesis of cancer is well-known due to their involvement in carcinogenesis. Although previous studies have discussed different functions of JNKs depending on cell type, the present study aimed to investigate the function of JNKs in nasopharyngeal carcinoma (NPC) cells, as well as their involvement in chemotherapy sensitivity to Adriamycin. The present results showed that Adriamycin administration reduced cell viability and led to elevated expressions of c-Jun, phosphorylated JNK and phosphorylated c-Jun, indicating an activated JNK pathway. Notably, JNK inhibition by SP600125 also reduced cell growth. Thus, Adriamycin treatment combined with SP600125 was more effective on cell growth inhibition than each agent alone. The apoptosis analysis confirmed the reduction in cell growth. Therefore, these data provide evidence that the JNK pathway activity is negatively associated with cell viability, and its decline could sensitize NPC cells to Adriamycin.

SUBMITTER: Liu Y

PROVIDER: S-EPMC5529981 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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MicroRNA-205-5p regulates the chemotherapeutic resistance of hepatocellular carcinoma cells by targeting PTEN/JNK/ANXA3 pathway.

Project description:Hepatocellular carcinoma (HCC) is a common malignant tumor of the digestive system, and patients with advanced HCC have a poor outlook, partly due to resistance to chemotherapeutic drugs. Previous studies have implicated microRNAs in the regulation of chemoresistance, and we have previously shown that microRNA (miR)-205-5p is down-regulated in multiple hepatoma cell lines. Here, we investigate whether miR-205-5p is involved in chemotherapeutic resistance in HCC. Expression of miR-205-5p was measured by real-time quantitative reverse transcription PCR and cell viability was determined using a CCK-8 cell viability assay. Expression of proteins in the PTEN/JNK/ANXA3 pathway were assessed via Western blotting. We found that miR-205-5p expression was down-regulated in all HCC cell lines investigated. In addition, miR-205-5p expression was upregulated by 5-fluorouracil (5-Fu) treatment in Bel-7402 (Bel) cells. Interestingly, miR-205-5p expression was increased in multidrug-resistant Bel-7402/5-Fu (Bel/Fu) cells, compared with Bel cells. We next demonstrated that sensitivity to 5-Fu was increased in Bel/Fu cells after treatment with a miR-205-5p inhibitor. Similarly, increased resistance to 5-Fu was observed in Bel cells after transfection with a miR-205-5p mimic. We injected nude mice with Bel/5-Fu cells to promote tumor growth, and found that co-treatment with a miR-205-5p antagomir and 5-Fu slowed tumor growth more than either treatment alone. Finally, we found that these effects were all associated with changes in the PTEN/JNK/ANXA3 pathway. In conclusion, inhibition of miR-205-5p may reverse chemotherapeutic resistance to 5-Fu, and this may occur via the PTEN/JNK/ANXA3 pathway.

| S-EPMC5622272 | biostudies-literature

Inhibition of PAD4 enhances radiosensitivity and inhibits aggressive phenotypes of nasopharyngeal carcinoma cells.

Project description:BackgroundNasopharyngeal carcinoma (NPC) is a tumor deriving from nasopharyngeal epithelium. Peptidyl-arginine deiminase 4 (PAD4) is a vital mediator of histone citrullination and plays an essential role in regulating disease process. Radiotherapy is an essential method to treat NPC. In this research, we explored the effect of PAD4 on NPC radiosensitivity.MethodsWe enrolled 50 NPC patients, established mice xenograft model, and purchased cell lines for this study. Statistical analysis and a series of experiments including RT-qPCR, clonogenic survival, EdU, Transwell, and wound healing assays were done.ResultsOur data manifested that PAD4 (mRNA and protein) presented a high expression in NPC tissues and cells. GSK484, an inhibitor of PAD4, could inhibit activity of PAD4 in NPC cell lines. PAD4 overexpression promoted the radioresistance, survival, migration, and invasion of NPC cells, whereas treatment of GSK484 exerted inhibitory effects on radioresistance and aggressive phenotype of NPC cells. Additionally, GSK484 could attenuate the effect of PAD4 of NPC cell progression. More importantly, we found that GSK484 significantly inhibited tumor size, tumor weight and tumor volume in mice following irradiation.ConclusionsPAD4 inhibitor GSK484 attenuated the radioresistance and cellular progression in NPC.

| S-EPMC7962337 | biostudies-literature

Inhibition of Musashi-1 enhances chemotherapeutic sensitivity in gastric cancer patient-derived xenografts.

Project description:Musashi-1 (MSI1), a neural RNA-binding protein, is considered a gastric and intestinal stem cell marker. Although the function of MSI1 in gastric cancer has attracted increasing interest, it is not known whether MSI1 can be used as a biomarker to monitor gastric cancer development and response to treatment. Here, the role of MSI1 in the chemotherapeutic sensitivity of gastric cancer was investigated. Patients with high MSI1 levels had poor outcomes, implicating the gene in the development and progression of the disease. We overexpressed and silenced MSI1 in the human gastric cancer cell lines MKN45 and HGC27, finding that knockdown reduced proliferation, invasion, and migration, while promoting apoptosis. A patient-derived xenograft gastric cancer model was constructed in which mice received chemical drugs, si-MSI1, or a drug-si-MSI1 combination. It was found that blocking MSI1 expression reduced gastric cancer drug tolerance. The combination treatment with si-MSI1 was superior to 5F-dUMP and cisplatin, either separately or in combination, indicating that including si-MSI1 was better than drug therapy alone. Transcriptome sequencing analysis showed that MSI1 altered cell cycle regulation and growth signal transduction, including that of blood vessel epicardial substance (BVES). These results suggest that MSI1 reduces the tolerance of gastric cancer to chemical drugs through modulation of MSI1/BVES signaling.

| S-EPMC9160935 | biostudies-literature

Inhibition of JNK-mediated autophagy enhances NSCLC cell sensitivity to mTORC1/2 inhibitors.

Project description:As the activation of autophagy contributes to the efficacy of many anticancer therapies, deciphering the precise role of autophagy in cancer therapy is critical. Here, we report that the dual mTORC1/2 inhibitors PP242 and OSI-027 decreased cell viability but did not induce apoptosis in the non-small cell lung cancer (NSCLC) cell lines H460 and A549. PP242 induced autophagy in NSCLC cells as demonstrated by the formation of massive vacuoles and acidic vesicular organelles and the accumulation of LC3-II. JNK was activated by PP242, and PP242-induced autophagy was blocked by inhibiting JNK pathway with SP600125 or JNK siRNA, suggesting that JNK activation is required for the mTORC1/2 inhibitor-mediated induction of autophagy in NSCLC cells. Inhibiting JNK or autophagy increased the sensitivity of H460 cells to mTORC1/2 inhibitors, indicating that JNK or autophagy promoted survival in NSCLC cells treated with mTORC1/2 inhibitors. Together, these data suggest that combining mTORC1/2 inhibitors with inhibitors of JNK or autophagy might be an effective approach for improving therapeutic outcomes in NSCLC.

| S-EPMC4928093 | biostudies-literature

Cisplatin sensitivity in nasopharyngeal carcinoma cells (NPC)

Project description:Transcriptional profiling of cisplatin sensitive NPCs 6-condition experiment, CNE2 vs. S16 cells at 0, 2 or 8 hr treatment. Biological replicates: 2 for each control (0 hr), 2 for each treatment (2 hr and 8 hr), independently grown and harvested, dye-swapped.

2013-08-13 | E-GEOD-49813 | biostudies-arrayexpress

Cisplatin sensitivity in nasopharyngeal carcinoma cells (NPC)

Project description:Transcriptional profiling of cisplatin sensitive NPCs

2013-08-13 | GSE49813 | GEO

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

Project description: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 3β (pGSK3β; 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.

| S-EPMC6683154 | biostudies-literature

Melatonin enhances sensitivity to fluorouracil in oesophageal squamous cell carcinoma through inhibition of Erk and Akt pathway.

Project description:Oesophageal squamous cell carcinoma (ESCC) is the sixth most common cause of cancer-associated death in the world and novel therapeutic alternatives are urgently warranted. In this study, we investigated the anti-tumour activity and underlying mechanisms of melatonin, an indoleamine compound secreted by the pineal gland as well as naturally occurring plant products, in ESCC cells and revealed that melatonin inhibited proliferation, migration, invasion and induced mitochondria-dependent apoptosis of ESCC cells in vitro and suppressed tumour growth in the subcutaneous mice model in vivo. Furthermore, after treatment with melatonin, the expressions of pMEK, pErk, pGSK3β and pAkt were significantly suppressed. In contrast, treatment of the conventional chemotherapeutic drug fluorouracil (5-Fu) resulted in activation of Erk and Akt, which could be reversed by co-treatment with melatonin. Importantly, melatonin effectively enhanced cytotoxicity of 5-Fu to ESCC in vitro and in vivo. Together, these results suggested that inhibition of Erk and Akt pathway by melatonin have an important role in sensitization of ESCC cells to 5-Fu. Combined 5-Fu and melatonin treatment may be appreciated as a useful approach for ESCC therapy that warrants further investigation.

| S-EPMC5133993 | biostudies-literature

The ferroptosis inducer erastin enhances sensitivity of acute myeloid leukemia cells to chemotherapeutic agents.

Project description:Acute myeloid leukemia (AML) is the most common type of leukemia in adults. Development of resistance to chemotherapeutic agents is a major hurdle in the effective treatment of patients with AML. The quinazolinone derivative erastin was originally identified in a screen for small molecules that exhibit synthetic lethality with expression of the RAS oncogene. This lethality was subsequently shown to occur by induction of a novel form of cell death termed ferroptosis. In this study we demonstrate that erastin enhances the sensitivity of AML cells to chemotherapeutic agents in an RAS-independent manner. Erastin dose-dependently induced mixed types of cell death associated with ferroptosis, apoptosis, necroptosis, and autophagy in HL-60 cells (AML, NRAS_Q61L), but not Jurkat (acute T-cell leukemia, RAS wild type), THP-1 (AML, NRAS_G12D), K562 (chronic myelogenous leukemia, RAS wild type), or NB-4 (acute promyelocytic leukemia M3, KRAS_A18D) cells. Treatment with ferrostatin-1 (a potent ferroptosis inhibitor) or necrostatin-1 (a potent necroptosis inhibitor), but not with Z-VAD-FMK (a general caspase inhibitor) or chloroquine (a potent autophagy inhibitor), prevented erastin-induced growth inhibition in HL-60 cells. Moreover, inhibition of c-JUN N-terminal kinase and p38, but not of extracellular signal-regulated kinase activation, induced resistance to erastin in HL-60 cells. Importantly, low-dose erastin significantly enhanced the anticancer activity of 2 first-line chemotherapeutic drugs (cytarabine/ara-C and doxorubicin/adriamycin) in HL-60 cells. Collectively, the induction of ferroptosis and necroptosis contributed to erastin-induced growth inhibition and overcame drug resistance in AML cells.

| S-EPMC4905356 | biostudies-literature

Inhibition of livin overcomes radioresistance in nasopharyngeal carcinoma cells.

Project description:BACKGROUND AND AIMS:Radiotherapy is one of the major remedies for the treatment of cancer, including nasopharyngeal carcinoma (NPC). Radioresistance occurs very often in target cells that is a large drawback in cancer treated with radiotherapy. Livin involves the over-growth of cancer cells. This study aims to investigate the role of livin in the radioresistance formation in NPC cells. METHODS:NPC cell lines were exposed to small doses of irradiation to establish a cell model of radioresistance, in which the role of livin in the development of radioresistance was evaluated. RESULTS:The expression of livin was observed in NPC cells, which was significantly increased after exposing to small doses of irradiation. A negative correlation was detected between livin and Fas expression in NPC cells. Livin formed a complex with heat shock factor-1 (HSF1, the transcription factor of Fas) in NPC cells after irradiation, which sped up ubiquitination of HSF1. Livin was involved in suppressing Fas expression in NPC cells with radioresistance. Exposure to livin inhibitors prevented radioresistance development and overcame the established radioresistance in NPC cells. CONCLUSIONS:Livin expression in NPC cells plays a critical role in the development of radioresistance. Depletion of livin increases the sensitiveness of NPC cells to irradiation. Target therapy against livin may have the translational potential for the treatment of NPC.

| S-EPMC7051067 | biostudies-literature

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