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Articles by R. Lotan
Total Records ( 4 ) for R. Lotan
  H Kadara , L Lacroix , C Behrens , L Solis , X Gu , J. J Lee , E Tahara , D Lotan , W. K Hong , I. I Wistuba and R. Lotan
 

Lung cancer continues to be a major deadly malignancy. The mortality of this disease could be reduced by improving the ability to predict cancer patients' survival. We hypothesized that genes differentially expressed among cells constituting an in vitro human lung carcinogenesis model consisting of normal, immortalized, transformed, and tumorigenic bronchial epithelial cells are relevant to the clinical outcome of non–small cell lung cancer (NSCLC). Multidimensional scaling, microarray, and functional pathways analyses of the transcriptomes of the above cells were done and combined with integrative genomics to incorporate the microarray data with published NSCLC data sets. Up-regulated (n = 301) and down-regulated genes (n = 358) displayed expression level variation across the in vitro model with progressive changes in cancer-related molecular functions. A subset of these genes (n = 584) separated lung adenocarcinoma clinical samples (n = 361) into two clusters with significant survival differences. Six genes, UBE2C, TPX2, MCM2, MCM6, FEN1, and SFN, selected by functional array analysis, were also effective in prognosis. The mRNA and protein levels of one these genes—UBE2C—were significantly up-regulated in NSCLC tissue relative to normal lung and increased progressively in lung lesions. Moreover, stage I NSCLC patients with positive UBE2C expression exhibited significantly poorer overall and progression-free survival than patients with negative expression. Our studies with this in vitro model have lead to the identification of a robust six-gene signature, which may be valuable for predicting the survival of lung adenocarcinoma patients. Moreover, one of those genes, UBE2C, seems to be a powerful biomarker for NSCLC survival prediction.

  N Chakravarti , H Kadara , D. J Yoon , J. W Shay , J. N Myers , D Lotan , N Sonenberg and R. Lotan
 

Curcumin has shown some promise in the prevention of oral carcinogenesis by mechanism(s) that are still not completely resolved. Messenger RNA translation is mediated in eukaryotes by the eIF4F complex composed of eukaryotic translation initiation factors eIF4E, eIF4G, and eIF4A. Overexpression of some of these components or the inactivation of initiation repressor proteins (4E-BP1) has been implicated in cancer development including oral carcinogenesis by affecting cell survival, angiogenesis, and tumor growth and invasion. In this study, we examined the possibility that curcumin affects the translational machinery differently in normal, immortalized normal, leukoplakia, and malignant cells. Curcumin treatment in vitro inhibited the growth of immortalized oral mucosa epithelial cells (NOM9-CT) and the leukoplakia cells (MSK-Leuk1s) as well as in the UMSCC22B and SCC4 cells derived from head and neck squamous cell carcinoma. Curcumin only exerted minor effects on the growth of normal oral epithelial cells (NOM9). In the immortalized, leukoplakia, and cancer cells, curcumin inhibited cap-dependent translation by suppressing the phosphorylation of 4E-BP1, eIF4G, eIF4B, and Mnk1, and also reduced the total levels of eIF4E and Mnk1. Our findings show that immortalized normal, leukoplakia, and malignant oral cells are more sensitive to curcumin and show greater modulation of protein translation machinery than the normal oral cells, indicating that targeting this process may be an important approach to chemoprevention in general and for curcumin in particular. Cancer Prev Res; 3(3); 331–8

  J Deng , J Fujimoto , X. F Ye , T. Y Men , C. S Van Pelt , Y. L Chen , X. F Lin , H Kadara , Q Tao , D Lotan and R. Lotan
 

Mouse models can be useful for increasing the understanding of lung tumorigenesis and assessing the potential of chemopreventive agents. We explored the role of inflammation in lung tumor development in mice with knockout of the tumor suppressor Gprc5a. Examination of normal lung tissue and tumors from 51 Gprc5a+/+ (adenoma incidence, 9.8%; adenocarcinoma, 0%) and 38 Gprc5a–/– mice (adenoma, 63%; adenocarcinoma, 21%) revealed macrophage infiltration into lungs of 45% of the Gprc5a–/– mice and 8% of Gprc5a+/+ mice and the direct association of macrophages with 42% of adenomas and 88% of adenocarcinomas in the knockout mice. Gprc5a–/– mouse lungs contained higher constitutive levels of proinflammatory cytokines and chemokines and were more sensitive than lungs of Gprc5a+/+ mice to stimulation of NF-B activation by lipopolysaccharide in vivo. Studies with epithelial cells cultured from tracheas of Gprc5a–/– and Gprc5a+/+ mice revealed that Gprc5a loss is associated with increased cell proliferation, resistance to cell death in suspension, and increased basal, tumor necrosis factor –induced, and lipopolysaccharide-induced NF-B activation, which were reversed partially in Gprc5a–/– adenocarcinoma cells by reexpression of Gprc5a. Compared with Gprc5a+/+ cells, the Gprc5a–/– cells produced higher levels of chemokines and cytokines and their conditioned medium induced more extensive macrophage migration. Silencing Gprc5a and the p65 subunit of NF-B in Gprc5a+/+ and Gprc5a–/– cells, respectively, reversed these effects. Thus, Gprc5a loss enhances NF-B activation in lung epithelial cells, leading to increased autocrine and paracrine interactions, cell autonomy, and enhanced inflammation, which may synergize in the creation of a tumor-promoting microenvironment. Cancer Prev Res; 3(4); 424–37. ©2010 AACR.

  J Fujimoto , M Kong , J. J Lee , W. K Hong and R. Lotan
 

Lung cancer is the leading cause of cancer death, developing over prolonged periods through genetic and epigenetic changes induced and exacerbated by tobacco exposure. Many epigenetic changes, including DNA methylation and histone methylation and acetylation, are reversible. The use of agents that can modulate these aberrations are a potentially effective approach to cancer chemoprevention. Combined epigenetic-targeting agents have gained interest for their potential to increase efficacy and lower toxicity. The present study applied recently developed statistical methods to validate the combined effects of the demethylating agent 5-aza-2-deoxycytidine (5-AZA-CdR, or AZA, or decitabine) and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA or vorinostat). This validation compared AZA alone with SAHA alone and with their combinations (at later or earlier time points and in varying doses) for inhibiting the growth of cell lines of an in vitro lung carcinogenesis system. This system comprises isogenic premalignant and malignant cells that are immortalized (earlier premalignant), transformed (later premalignant), and tumorigenic human bronchial epithelial cells [immortalized BEAS-2B and its derivatives 1799 (immortalized), 1198 (transformed), and 1170-I (tumorigenic)]. AZA alone and SAHA alone produced a limited (<50%) inhibition of cell growth, whereas combined AZA and SAHA inhibited cell growth more than either agent alone, reaching 90% inhibition under some conditions. Results of drug interaction analyses in the Emax model and semiparametric model supported the conclusion that drug combinations exert synergistic effects (i.e., beyond additivity in the Loewe model). The present results show the applicability of our novel statistical methodology for quantitatively assessing drug synergy across a wide range of doses of agents with complex dose-response profiles, a methodology with great potential for advancing the development of chemopreventive combinations. Cancer Prev Res; 3(8); 917–28. ©2010 AACR.

 
 
 
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