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1.  Proteasome Inhibitor MG132 Induces Apoptosis and Inhibits Invasion of Human Malignant Pleural Mesothelioma Cells 
Translational Oncology  2008;1(3):129-140.
Malignant pleural mesothelioma (MPM) is an aggressive malignancy tightly associated with asbestos exposure. The increasing incidence of MPM and its resistance to all therapeutic modalities necessitate an urgent development of new treatments for MPM. Proteasome inhibitors (PIs) have emerged as promising agents for treating human cancers that are refractory to current chemotherapies. In this study, we characterized MG132, a commonly used PI, for its proapoptotic and anti-invasion activities in NCI-H2452 and NCI-H2052 human thoracic MPM cell lines to determine the therapeutic effect of PIs on MPM. We found that as low as 0.5 µM MG132 caused a significant apoptosis in both cell lines as evidenced by DNA damage, cleavage of poly ADP-ribose polymerase and caspases 3, 7, and 9, and mitochondrial release of Smac/DIABLO and Cytochrome c. Mitochondrial caspase activation was found to be the underlying mechanism of the MG132-induced apoptosis. Mcl-1, among the Bcl-2 and IAP (inhibitor of apoptosis protein) antiapoptotic family proteins tested, was proved to be a major inhibitor of the MG132-induced apoptosis in MPM cells. Meanwhile, subapoptotic doses of MG132 inhibited the invasion of both MPM cell lines through reducing Rac1 activity. These observations demonstrate that MG132 possesses proapoptotic and anti-invasion activities in human MPM cells, therefore encouraging further investigations on the value of PIs for treating MPM.
PMCID: PMC2533141  PMID: 18795123
2.  Aberrant Gene Expression in Human Non Small Cell Lung Carcinoma Cells Exposed to Demethylating Agent 5-Aza-2′-Deoxycytidine 
Neoplasia (New York, N.Y.)  2004;6(4):412-419.
Abstract
The identification of genes undergoing genetic or epigenetic alterations and contributing to the development of cancer is critical to our understanding of the molecular mechanisms of carcinogenesis. A new approach in identifying alterations of genes that might be relevant to the process of tumor development was used in this study by examining the gene expression profile in human lung cancer cells exposed to 5-aza-2′-deoxycytidine (5-aza-dC). A cDNA array analysis was carried out on 5-aza-dC-treated and untreated non small cell lung cancer (NSCLC) cell line NCI-H522. Sixteen and 14 genes were upregulated and downregulated, respectively, by 5-aza-dC treatment. Among them, downregulation of tyrosine protein kinase ABL2 (ABL2) gene and upregulation of hint/protein kinase C inhibitor 1 (Hint/PKCI-1), DVL1, TIMP-1, and TRP-1 genes were found in expanded observations in two or three of five 5-aza-dC-treated NSCLC cell lines. Among these genes, we found that cDNA transfer of Hint/PKCI-1 resulted in a significant in vitro growth inhibition in two cell lines exhibiting 5-aza-dC-induced upregulation of Hint/PKCI-1 and significantly reduced in vivo tumorigenicity of one NSCLC cell line. Hint/PKCI-1, which is the only other characterized human histidine triad (HIT) nucleotide-binding protein in addition to tumor-suppressor gene FHIT, might be involved in lung carcinogenesis.
PMCID: PMC1502114  PMID: 15256063
Human non small cell lung carcinoma; 5-aza-2′-deoxycytidine; cell growth inhibition; ABL2 gene; Hint/PKCI-1 gene
3.  TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages 
BMC Cancer  2013;13:140.
Background
Malignant pleural mesothelioma (MPM) is an aggressive malignancy closely associated with asbestos exposure and extremely resistant to current treatments. It exhibits a steady increase in incidence, thus necessitating an urgent development of effective new treatments.
Methods
Proteasome inhibitors (PIs) and TNFα-Related Apoptosis Inducing Ligand (TRAIL), have emerged as promising new anti-MPM agents. To develop effective new treatments, the proapoptotic effects of PIs, MG132 or Bortezomib, and TRAIL were investigated in MPM cell lines NCI-H2052, NCI-H2452 and NCI-H28, which represent three major histological types of human MPM.
Results
Treatment with 0.5-1 μM MG132 alone or 30 ng/mL Bortezomib alone induced a limited apoptosis in MPM cells associated with the elevated Mcl-1 protein level and hyperactive PI3K/Akt signaling. However, whereas 10–20 ng/ml TRAIL alone induced a limited apoptosis as well, TRAIL and PI combination triggered a robust apoptosis in all three MPM cell lines. The robust proapoptotic activity was found to be the consequence of a positive feedback mechanism-governed amplification of caspase activation and cleavage of both Mcl-1 and Akt proteins, and exhibited a relative selectivity in MPM cells than in non-tumorigenic Met-5A mesothelial cells.
Conclusion
The combinatorial treatment using TRAIL and PI may represent an effective new treatment for MPMs.
doi:10.1186/1471-2407-13-140
PMCID: PMC3665596  PMID: 23517112
Malignant pleural mesothelioma; Apoptosis; Trail; Proteasome inhibitor; Mcl-1; Akt
4.  The changes of Th17 cells and the related cytokines in the progression of human colorectal cancers 
BMC Cancer  2012;12:418.
Background
The role of Th17 cells in colorectal tumorigenesis and development still remains unclear, despite the fact that it has been established in the pathogenesis of autoimmune diseases.
Methods
We first analyzed Th17 cells and Treg cells using flow cytometry in the circulation of colorectal adenoma (CRA) and colorectal carcinoma (CRC) patients and healthy controls, and the frequency of Th17 cells in peripheral blood mononuclear cells (PBMCs) stimulated by anti-CD3 plus anti-CD28 and treated by IL-1β, IL-6, and TGF-β in different concentrations. We then detected cytokines IL-1β, IL-6, IL-17A, IL-21, IL-23 or TGF-β by ELISA in sera and supernatants from both normal and tumor tissues cultured ex vivo.
Results
It was found that the percentage of Th17 and Treg cells increased in the circulation of both CRA and CRC patients; the increase of Th17 cells in the circulation occurred in early stages, whereas the increase of Treg cells in the circulation and the increase of Th17 cells in tumor tissues occurred in advanced stages. The subsequent cytokine profiling showed that, along CRC progression, IL-1β, IL-17A and IL-23 underwent a similar change, while IL-6 in CRC exhibited an opposite change, with Th17 cells. In addition, high levels of TGF-β and IL-17A were detected in tumor tissues rather than in normal mucosa. The in vitro experiment further demonstrated that IL-1β, IL-6 or TGF-β modulated Th17 cell expansion in PBMC.
Conclusions
Our study reveals a unique change of Th17 cells, which is regulated possibly by IL-1β, IL-6 and TGF-β in the progression of CRC.
doi:10.1186/1471-2407-12-418
PMCID: PMC3488332  PMID: 22994684
Colorectal adenoma; Colorectal cancer; Th17 cells; Treg cells; Cytokines
5.  CHK2 kinase expression is down-regulated due to promoter methylation in non-small cell lung cancer 
Molecular Cancer  2004;3:14.
Background
CHK2 kinase is a tumor suppressor that plays important role in DNA damage signaling, cell cycle regulation and DNA damage induced apoptosis. CHK2 kinase expression was known to be ubiquitous in mammalian cells. CHK2-/- cells were remarkably resistant to DNA damage induced apoptosis, mimicking the clinical behavior of non-small cell lung cancer to conventional chemo and radiation therapy.
Result
We reported that the CHK2 expression is diminished or absent in both non-small cell lung cancer (NSCLC) cell lines and clinical lung cancer tumor specimens. The absent CHK2 expression in NSCLC was due to hypermethylation of the CHK2 gene promoter, preventing from binding of a transcriptional factor, leading to silence of the CHK2 gene transcription.
Conclusion
Since the CHK2 null mice showed a remarkable radioresistance, which bear significant similarity to clinical behavior of NSCLC, down-regulation of CHK2 kinase expression by CHK2 gene silencing and methylation in non-small cell lung cancer suggest a critical role of CHK2 kinase in DNA damage induced apoptosis and a novel mechanism of the resistance of NSCLC to DNA damage based therapy.
doi:10.1186/1476-4598-3-14
PMCID: PMC419366  PMID: 15125777

Results 1-5 (5)