tretinoin and Nasopharyngeal-Neoplasms

Cancer cells prefer glycolysis to support their proliferation. Our previous studies have shown that the long palate, lung, and nasal epithelial cell clone 1 (LPLUNC1) can upregulate prohibitin 1 (PHB1) expression to inhibit the proliferation of nasopharyngeal carcinoma (NPC) cells. Given that PHB1 is an important regulator of cell energy metabolism, we explored whether and how LPLUNC1 regulated glucose glycolysis in NPC cells. LPLUNC1 or PHB1 overexpression decreased glycolysis and increased oxidative phosphorylation (OXPHOS)-related protein expression in NPC cells, promoting phosphorylated PHB1 nuclear translocation through 14-3-3σ. LPLUNC1 overexpression also increased p53 but decreased c-Myc expression in NPC cells, which were crucial for the decrease in glycolysis and increase in OXPHOS-related protein expression induced by LPLUNC1 overexpression. Finally, we found that treatment with all-trans retinoic acid (ATRA) reduced the viability and clonogenicity of NPC cells, decreased glycolysis, and increased OXPHOS-related protein expression by enhancing LPLUNC1 expression in NPC cells. Therefore, the LPLUNC1-PHB1-p53/c-Myc axis decreased glycolysis in NPC cells, and ATRA upregulated LPLUNC1 expression, ATRA maybe a promising drug for the treatment of NPC.

Topics: Autoantigens; Cell Line, Tumor; Cell Proliferation; Epithelial Cells; Fatty Acid-Binding Proteins; Gene Expression Regulation, Neoplastic; Glycolysis; Humans; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Proto-Oncogene Proteins c-myc; Tretinoin; Tumor Suppressor Protein p53

Human SPLUNC1 can suppress nasopharyngeal carcinoma (NPC) tumor formation; however, the correlation between SPLUNC1expression and NPC patient prognosis has not been reported. In the present study, we used a large-scale sample of 1015 tissue cores to detect SPLUNC1 expression and its association with patient prognosis. SPLUNC1 expression was reduced in NPC samples compared to nontumor nasopharyngeal epithelium tissues. Positive expression of SPLUNC1 in NPC predicted a better prognosis (disease-free survival, P = 0.034; overall survival, P = 0.048). Cox's proportional hazards model revealed that SPLUNC1 could be a significant prognostic factor affecting disease-free survival (P = 0.027). A cDNA micro-array analyzed by significant analysis of micro-array (SAM) and ingenuity pathway analysis (IPA) revealed that an indirect interaction existed between SPLUNC1 and retinoic acid (RA) in the cancer regulatory network. To further investigate the molecular mechanisms involved, we utilized several bioinformatics tools and identified 12 retinoid X receptors heterodimer binding sites in the promoter region of the SPLUNC1 gene. The transcriptional activity of the SPLUNC1 promoter was up-regulated significantly by all-trans-retinoic acid (ATRA). SPLUNC1 and retinoic acid receptor expression were induced significantly by ATRA, and removal of ATRA led to a progressive loss of SPLUNC1 and retinoic acid receptor expression. ATRA inhibited proliferation and induced the differentiation of NPC cells. Interestingly, over-expression of SPLUNC1 sensitized NPC cells to ATRA, whereas knockdown of SPLUNC1 in HNE1 cells increased cell viability. Under SPLUNC1 knockdown conditions, differentiation was reversed by ATRA treatment. We concluded that SPLUNC1 could potentially predict prognosis for NPC patients and play an important role in ATRA-induced growth inhibition and differentiation in NPC cells.

Topics: 5' Untranslated Regions; Adolescent; Adult; Aged; Binding Sites; Carcinoma; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Epithelial Cells; Female; Gene Expression Regulation, Neoplastic; Glycoproteins; Humans; Lymphatic Metastasis; Male; Middle Aged; Nasopharyngeal Neoplasms; Neoplasm Proteins; Phosphoproteins; Prognosis; Promoter Regions, Genetic; Recombinant Fusion Proteins; Retinoid X Receptors; RNA Interference; RNA, Small Interfering; Tretinoin; Young Adult

The purpose of this study was to determine the effect of all-trans retinoid acid (ATRA) on two nasopharyngeal cancer (NPC) cell lines and to evaluate the synergistic effect of ATRA used in combination with cisplatin, a standard chemotherapeutic agent for NPC. Two NPC cell lines (NPC-TW01 and NPC-TW04) were used, and the MTT assay was used to analyze cell growth inhibition under various concentrations of ATRA and cisplatin. Under low concentrations of ATRA, the growth of both cell lines was significantly inhibited. When ATRA was used in combination with cisplatin, the resulting synergistic effects were robust and significant. Only a low concentration of ATRA was required to produce a synergistic effect when combined with cisplatin, indicating the potential usefulness of a combination therapy regimen. Therefore, the combination of ATRA and cisplatin is a viable treatment option for NPC and should be further investigated.

Topics: Antineoplastic Agents; Carcinoma; Cell Line, Tumor; Cisplatin; Drug Synergism; Drug Therapy, Combination; Growth Inhibitors; Humans; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Tretinoin; Tumor Cells, Cultured

Nasopharyngeal carcinoma is closely associated with infection with Epstein-Barr Virus (EBV); however, the mechanism is still unclear. Here, we report that the EBV oncoprotein, latent membrane protein 1 (LMP1), suppresses apoptotic cell death provoked by all-trans retinoic acid (ATRA) in NPC cells. For this purpose, LMP1 downregulated levels of Bak whilst it upregulated levels of Bcl2, lowering the ratio of Bak to Bcl2. In addition, LMP1 suppressed ATRA-mediated activation of Caspase 9, Caspase 3, and PARP but not Caspase 8 in Ad-AH cells, suggesting that LMP1 acts by blocking the activation of intrinsic apoptosis pathway by ATRA. These effects were almost completely abolished when levels of retinoic acid receptor-β(2) (RAR-β(2)) in the LMP1-expressing cells were recovered by either exogenous gene expression or treatment with a universal DNMT inhibitor, 5-Aza-2'dC, indicating that LMP1 executes its antiapoptotic effects by downregulating levels of RAR-β(2) via DNA methylation.

Topics: Apoptosis; bcl-2 Homologous Antagonist-Killer Protein; Carcinoma; Caspases; Cell Line, Tumor; DNA Methylation; Down-Regulation; Humans; Nasopharyngeal Neoplasms; Poly(ADP-ribose) Polymerases; Receptors, Retinoic Acid; Tretinoin; Viral Matrix Proteins

It was reported that chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1(SDF-1) were involved in the proliferation, differentiation, and metastasis of tumor. This study was designed to observe the expression of CXCR4 in NPC cells with different differentiation grade and proliferative ability to primitively clarify the relationship between CXCR4 and the malignity of NPC cells.. After treated with all-trans-retinoic acid(RA) and telomerase antisense oligodeoxynucleotide (ASODN) respectively, the expression of CXCR4 mRNA and CXCR4 protein in NPC CNE1 and CNE2Z cells were determined by in situ hybridization and immunohistochemistry, respectively; the distribution of cell cycle was examined with flow cytometry and the proliferation of cells was identified by MTT method.. CXCR4 mRNA and CXCR4 protein were strongly expressed in both CNE1 and CNE2Z cells, and their expression in CNE2Z cells was stronger than that in CNE1 cells. After treated with 1x10(-5) mol/L and 1x10(-4) mol/L RA, CNE1 cells were arrested in G1 phase and CNE2Z cells in S phase, while the CXCR4 mRNA expression was significantly decreased in both CNE1 and CNE2Z cells compared with control group cells (P< 0.01). The effect of 1x10(-4) mol/L RA was more powerful than that of 1x10(-5) mol/L RA. After treated with ASODN, the proliferation of CNE1 and CNE2Z cells was inhibited, and the expression of CXCR4 protein was decreased compared with the control (P< 0.01).. CXCR4 is highly expressed in NPC cells,and its expression was associated with differentiation grade and proliferation ability of NPC cells.

Topics: Cell Cycle; Cell Differentiation; Cell Line, Tumor; Humans; Nasopharyngeal Neoplasms; Oligonucleotides, Antisense; Receptors, CXCR4; RNA, Messenger; Telomerase; Tretinoin

To investigate the effects of retinoic acid (RA) on the growth, morphology, oncogene expression and regulation of nasopharyngeal carcinoma cells.. Nasopharyngeal carcinoma cell line (HNE1) was induced by RA. The RA-treated and control cells were established and cellular morphology and growth patterns were defined. Oncogene expression and regulation were detected by Northern hybridization and DNase-I hypersensitive site analysis.. RA markedly inhibited cell growth. The growth of HNE1 cells was reduced to 50% of the control level on the 4th day of RA (10(-4) mol/L) treatment. After 4 days of treatment, the rapidly growing polygonal cells were reversed into a slow growing phenotype, with flattened morphology similar to fibroblast-like cells. Northern hybridization showed that c-myc and c-Ha-ras expression was high in HNE1 cells and undetectable in normal blood cells. c-myc was down-regulated at 48 h of RA treatment. In contrast, the c-Ha-ras was not affected. DNase I hypersensitive site analysis detected changes in the regulatory elements of c-myc and c-Ha-ras genes. 5 hypersensitive sites were found in the c-myc of HNE1 cells, while 3 hypersensitive sites disappeared upon HNE1 induction. However, only 1 hypersensitive site was found in c-Ha-ras of RA treated cells and controls. In normal peripheral white blood cells, no DNase I hypersensitive sites were found in the inactive c-myc and c-Ha-ras gene.. RA can induce differentiation in a nasopharyngeal carcinoma cell line at high concentration of RA; HNE1 shows some similar patterns of DNase I hypersensitive sites with the common one in other types of cells expressing c-myc. The repression of c-myc expression with induction is accompanied by the loss of 3 DNase-I hypersensitive sites; c-myc has more than one inactive conformation.

Topics: Antineoplastic Agents; Cell Division; Cell Size; Deoxyribonuclease I; DNA, Neoplasm; Dose-Response Relationship, Drug; Gene Silencing; Genes, myc; Humans; Nasopharyngeal Neoplasms; RNA, Messenger; Time Factors; Tretinoin; Tumor Cells, Cultured

To observe the differentiation-inducing effect of Stepholidine (ST) and Retinoic Acid (RA) on laryngeal and nasopharyngeal carcinoma, the expression of oncogene (C-myc, bcl-2) protein and tumor suppressor gene (p53) was done by using flow cytometry and ABC immunohistochemical methods combined with image analysis technique. The results indicated that after treated with ST and RA, the cells became well-differentiated, the cell growth was suppressed, contact suppress was partially recovered, colony forming was decreased, protooncogenes (C-myc bcl-2) protein was decreased, tumor suppressor gene (p53) protein was increased. No significant difference was observed between the cells treated with ST and TA. We believed that the Chinese medicine-Stephania might be expected to become a new prospective differentiation inducer in carcinoma of head and neck.

Topics: Berberine; Cell Differentiation; Cell Division; Humans; Laryngeal Neoplasms; Nasopharyngeal Neoplasms; Proto-Oncogene Proteins c-bcl-2; Tretinoin; Tumor Cells, Cultured; Tumor Suppressor Protein p53

N(4-hydroxycarbophenyl) retinamide (RII) is a new synthetic analog of retinoids with low toxicity. Its effect on the biological properties associated with tumor malignant behavior of human nasopharyngeal carcinoma cell lines (HNCs), including CNE-2Z parent cell lines and their variants L2, H2, L4 was studied. RII (10(-5) mol/L) caused detectable morphologic differentiation of HNCs. It inhibited growth of HNCs in vitro and decreased ability of these cells to penetrate matrigel-coated filters by using a reconstituted basement membrane invasion assay. These results suggested that RII might be a kind of useful anticancer drug.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Humans; Nasopharyngeal Neoplasms; Neoplasm Invasiveness; Tretinoin; Tumor Cells, Cultured

To evaluate the effects of gap junctional intercellular communication (GJIC) on the growth, invasion and metastasis of tumor, human nasopharyngeal carcinoma (HNPC) parent cell line (CNE-2Z) and its variants (L2, H2, L4) with different invasive and metastatic potential were examined in vitro. Only a few intermediate junction (IJ) but no gap junction (GJ) structures were observed under EM. The parent line cells showed marked GJIC, while its variants lacked this function by SLDT technique. It was further shown that L2 cell line (variant with high invasive potential) had lower concentration of cytosolic free calcium ([Ca2+]i) compared to H2, L4 cell lines (variants with medium and low invasive potential, respectively). It reflected that some correlation may exist between [Ca2+]i level and the invasive potential of HNPC cell lines. The effect of RII on GJIC of HNPC was also investigated. After 3-7 ds of RII (0.0001 mol/L) treatment, there was no change in the number of GJs. The GJIC function of CNE-2Z weakened and then disappeared finally with prolonged RII treatment. The level of [Ca2+]i in HNPC cells apparently fell after 6h of RII treatment, and rose to original level with persistent RII treatment. Whether the fluctuating of [Ca2+]i level relates the inhibitory effect of RII treatment. Treatment on the growth and invasion needs to be further studied.

Topics: Calcium; Carcinoma, Squamous Cell; Cell Communication; Gap Junctions; Humans; Nasopharyngeal Neoplasms; Neoplasm Invasiveness; Tretinoin; Tumor Cells, Cultured

Topics: Animals; Antineoplastic Agents; Nasal Cavity; Nasopharyngeal Neoplasms; Nitrosamines; Nose Neoplasms; Precancerous Conditions; Rats; Rats, Inbred Strains; Tretinoin

The in vitro proliferation and colony-forming activity (plating efficiency) of Epstein-Barr virus (EBV) nuclear antigen-positive nasopharyngeal hybrid cells were inhibited by one of the retinoid, polyprenoic acid; E5166. It was dependent on retinoid concentration. Furthermore, an induction of EBV early antigen after treatment with 4 mM n-butyrate was markedly suppressed by E5166 and this was similar to the previously reported effects of retinoid acid on iododeoxyuridine (IUDR) and 12-O-tetra-decanoyl-phorbol-13-acetate (TPA) induction. These results support to lead a clinical application of E5166 for combination chemotherapy in patients with nasopharyngeal carcinoma.

Topics: Antigens, Viral, Tumor; Butyrates; Butyric Acid; Carcinoma; Cells, Cultured; Fluorescent Antibody Technique; Herpesvirus 4, Human; Humans; Nasopharyngeal Neoplasms; Tretinoin; Tumor Virus Infections

Topics: Antigens, Viral; Butyrates; Cells, Cultured; Herpesvirus 4, Human; Humans; Interferon Type I; Nasopharyngeal Neoplasms; Tretinoin

Topics: Butyrates; Butyric Acid; Carcinoma; China; Croton Oil; Herpesvirus 4, Human; Humans; Nasopharyngeal Neoplasms; Plant Extracts; Plants, Medicinal; Stimulation, Chemical; Tretinoin; Virus Activation; Vitamin A Deficiency

Induction of Epstein-Barr virus (EBV) early antigen after treatment with various combinations of croton oil and n-butyrate was markedly inhibited by retinoids 7901, 7902, Ro 10-9359 and Ro 11-1430. Possible administration of retinoids to virus capsid antigen IgA antibody-positive individuals in high-risk areas for nasopharyngeal carcinoma to prevent EBV activation and development of this cancer is discussed.

Topics: Butyrates; Croton Oil; Etretinate; Herpesvirus 4, Human; Humans; Nasopharyngeal Neoplasms; Tretinoin; Virus Activation; Vitamin A