Multifunctional role of Bcl-2 in malignant transformation and tumorigenesis of Cr(VI)-transformed lung cells

• Published in: PloS one Vol. 7; no. 5; p. e37045
• Main Authors: Medan, Djordje, Luanpitpong, Sudjit, Azad, Neelam, Wang, Liying, Jiang, Bing-Hua, Davis, Mary E, Barnett, John B, Guo, Lan, Rojanasakul, Yon
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.05.2012; Public Library of Science (PLoS)
• Subjects: Air pollution; Angiogenesis; Animals; Antigens; Apoptosis; Apoptosis - drug effects; B cells; B-cell lymphoma; Bcl-2 protein; Biology; Breast cancer; Carcinogens; Cell growth; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Transformation, Neoplastic - drug effects; Chromium; Chromium - toxicity; Chronic exposure; Cytochrome; Cytotoxicity; Ectopic expression; Epithelial cells; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockdown Techniques; Gene Silencing; Genetic engineering; Genetic transformation; Health maintenance organizations; Hexavalent chromium; Humans; Invasiveness; Lung - pathology; Lung cancer; Lung carcinoma; Lung Neoplasms - blood supply; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lymphocytes B; Lymphoma; Male; Medicine; Mice; Morphology; Mutation; Neoplasm Invasiveness; Neovascularization, Pathologic - metabolism; Non-Hodgkin's lymphomas; Outdoor air quality; p53 Protein; Pathology; Pharmaceutical sciences; Physiology; Properties (attributes); Proto-Oncogene Proteins c-bcl-2 - deficiency; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Studies; Transformation; Transformed cells; Tumor proteins; Tumor Suppressor Protein p53 - metabolism; Tumorigenesis; West Virginia; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0037045

B-cell lymphoma-2 (Bcl-2) is an antiapoptotic protein known to be important in the regulation of apoptosis in various cell types. However, its role in malignant transformation and tumorigenesis of human lung cells is not well understood. We previously reported that chronic exposure of human lung epithelial cells to the carcinogenic hexavalent chromium Cr(VI) caused malignant transformation and Bcl-2 upregulation; however, the role of Bcl-2 in the transformation is unclear. Using a gene silencing approach, we showed that Bcl-2 plays an important role in the malignant properties of Cr(VI)-transformed cells. Downregulation of Bcl-2 inhibited the invasive and proliferative properties of the cells as well as their colony forming and angiogenic activities, which are upregulated in the transformed cells as compared to control cells. Furthermore, animal studies showed the inhibitory effect of Bcl-2 knockdown on the tumorigenesis of Cr(VI)-transformed cells. The role of Bcl-2 in malignant transformation and tumorigenesis was confirmed by gene silencing experiments using human lung carcinoma NCI-H460 cells. These cells exhibited aggressive malignant phenotypes similar to those of Cr(VI)-transformed cells. Knockdown of Bcl-2 in the H460 cells inhibited malignant and tumorigenic properties of the cells, indicating the general role of Bcl-2 in human lung tumorigenesis. Ingenuity Pathways Analysis (IPA) revealed potential effectors of Bcl-2 in tumorigenesis regulation. Additionally, using IPA together with ectopic expression of p53, we show p53 as an upstream regulator of Bcl-2 in Cr(VI)-transformed cells. Together, our results indicate the novel and multifunctional role of Bcl-2 in malignant transformation and tumorigenesis of human lung epithelial cells chronically exposed to Cr(VI).