BackgroundCapsaicin (8-methyl-N-vanillyl-6-nonenamide) is one of the main pungent components of chili peppers and has been shown to exert various effects on numerous physiological processes. Recent studies have focused on the chemopreventive effects of capsaicin, which can combat growth in various human cancer cell systems. The tribbles-related protein 3 (TRIB3) is evolutionarily conserved from Drosophila to humans. In the latter, TRIB3 is a key determinant in numerous cellular processes, including apoptosis.PurposeThe aim of this study was to examine the importance of TRIB3 in the antitumor efficacy of capsaicin in human cancer cells, and further assess potential mechanism(s) underlying the capsaicin-induced upregulation of TRIB3.MethodsHuman cancer cell lines were treated with capsaicin, then evaluated for levels of TRIB3 and molecules related to apoptosis or signaling pathways. The impact of TRIB3 on capsaicin-induced apoptosis was investigated using si-RNA or overexpression of TRIB3.ResultsIt is the first time to show that TRIB3 is targeted by capsaicin to promote apoptosis. Capsaicin promotes apoptotic cell death by upregulating TRIB3 expression in cancer cells. Overexpression of TRIB3 enhances capsaicin-induced apoptosis, and TRIB3 knockdown experiments demonstrate that the effect of capsaicin in apoptotic cell death is correlated with the induction of TRIB3 in cancer cells. Finally, enhancements in gene expression and protein stability are involved in the capsaicin-induced upregulation of TRIB3.ConclusionOur results show that the capsaicin-induced upregulation of TRIB3 triggers apoptosis and thereby contributes to the suppression of cell growth in cancer cell lines.

Gastric cancer is one of the most common human malignancies, and its prevalence has been shown to be well-correlated with cancer-related deaths worldwide. Regrettably, the poor prognosis of this disease is mainly due to its late diagnosis at advanced stages after the cancer has already metastasized. Recent research has emphasized the identification of cancer biomarkers in the hope of diagnosing cancer early and designing targeted therapies to reverse cancer progression. One member of a family of growth-related nicotinamide adenine dinucleotide (NADH or hydroquinone) oxidases is tumor-associated NADH oxidase (tNOX; ENOX2). Unlike its counterpart CNOX (ENOX1), identified in normal rat liver plasma membranes and shown to be stimulated by growth factors and hormones, tNOX activity purified from rat hepatoma cells is constitutively active. Its activity is detectable in the sera of cancer patients but not in those of healthy volunteers, suggesting its clinical relevance. Interestingly, tNOX expression was shown to be present in an array of cancer cell lines. More importantly, inhibition of tNOX was well correlated with reduced cancer cell growth and induction of apoptosis. RNA interference targeting tNOX expression in cancer cells effectively restored non-cancerous phenotypes, further supporting the vital role of tNOX in cancer cells. Here, we review the regulatory role of tNOX in gastric cancer cell growth.

Abstract. The identification of prognostic markers and establishing their value as therapeutic targets improves therapeutic efficacy against human cancers. Ribophorin II (RPN2) has been demonstrated to be a prognostic marker of human cancer, including breast and pancreatic cancers. The present study aimed to evaluate RPN2 expression in gastric cancer and to examine the possible correlation between RPN2 expression and the response of cells to clinical anticancer drugs, which has received little research attention at present. The gastric cancer AGS, TMC-1, SNU-1, TMK-1, SCM-1, MKN-45 and KATO III cell lines were used as a model to elucidate the role of RPN2 in the response of cells to six common chemotherapeutic agents, comprising oxaliplatin, irinotecan, doxorubicin, docetaxel, cisplatin and 5-fluorouricil. The functional role of RPN2 was assessed by silencing RPN2 using small interfering RNA (siRNA), and the cytotoxicity was determined by an MTS assay and analysis of apoptosis. Molecular events were evaluated by western blotting. All the anticancer drugs were found to exert a concentration-dependent decrease on the cell survival rate of each of the cell lines tested, although the RPN2 levels in the various cell lines were not directly correlated with responsiveness to clinical anticancer drugs, based on the calculated IC 50 values. siRNA-mediated RPN2 downregulation enhanced cisplatin-induced apoptosis in AGS cells, but did not markedly decrease the cell survival rates of these cells in response to the tested drugs. Furthermore, RPN2 silencing in MKN-45 cells resulted in no additional increase in the cisplatin-induced apoptosis and survival rates. It was also found that RPN2 depletion increased anticancer drug-mediated cytotoxicity in gastric cancer cell lines. However, the predictive value of RPN2 expression in cancer therapy is questionable in gastric cancer models. IntroductionThe human ribophorin II (RPN2) gene has been localized to chromosome 20ql2-13.1, a region that is frequently deleted in patients with myeloid malignancies (1-4). The gene, which was cloned in 1987 (5), encodes a type I integral membrane protein that is found only in the rough endoplasmic reticulum (ER). Analysis of the structural and topological features of the gene has revealed RPN2 to be a unique integral rough ER membrane glycoprotein that is involved in translocation and the maintenance of the structural uniqueness of the rough ER (5,6). Subsequent biochemical studies have demonstrated that the RPN2 protein is a component of an N-oligosaccharyl transferase complex that conjugates high mannose oligosaccharides to asparagine residues in the N-X-S/T consensus motif of nascent polypeptide chains (7,8).In addition to its association with myeloid disorders, RPN2 has been demonstrated to be a prognostic marker of human breast (9) and pancreatic cancers (10). RPN2 has also been revealed to contribute to the resistance of tumor cells to chemotherapeutic agents, including docetaxel and taxane, in animal models of breast (11) and ovarian (12) ...

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