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

Medan D, Luanpitpong S, Azad N, Wang L, Jiang BH, Davis ME, Barnett JB, Guo L, Rojanasakul Y - PLoS ONE (2012)

Bottom Line: 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.Ingenuity Pathways Analysis (IPA) revealed potential effectors of Bcl-2 in tumorigenesis regulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia, United States of America.

ABSTRACT
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).

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Ingenuity Pathways Analysis software output for the downstream components of human Bcl-2-interactome.Twenty molecules of downstream components were reported to date and were labeled in orange, while upstream molecules were labeled in green.
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pone-0037045-g008: Ingenuity Pathways Analysis software output for the downstream components of human Bcl-2-interactome.Twenty molecules of downstream components were reported to date and were labeled in orange, while upstream molecules were labeled in green.

Mentions: In order to establish a strategy towards a better understanding of the mechanism(s) involved in Bcl-2's contribution to tumorigenesis, we performed an extensive PubMed database search for possible molecular targets. The initial query for Bcl-2 returned 33,970 hits! We realized that other approaches may need to be evaluated given the complexity of Bcl-2 cellular role(s). Following the analysis of available options, we turned to Ingenuity Pathways Analysis (IPA). IPA integrates the primary literature into easily searched and visualized networks allowing for orders of magnitude faster evaluation of cellular signaling cascades. The initial IPA query of Bcl-2's interactions (IPA v8.6) returned 741 hits. In order to make the network more relevant to our model, we filtered for only those interactions reported in humans (Figure 7). This reduced the interaction network to 56 molecules organized by cellular localization (Bcl-2-interactome). Given that we selectively targeted Bcl-2 and observed significant consequences on tumor-associated properties, we asked IPA to map only the downstream components of human Bcl-2-interactome known to date (Figure 8). The query returned 20 molecules. As we progressed from the initial overwhelming complexity of data to the more manageable and relevant Figure 6B, the current mechanistic evidence of Bcl-2's role in tumorigenesis emerged, as did a new approach to scientific query.


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

Medan D, Luanpitpong S, Azad N, Wang L, Jiang BH, Davis ME, Barnett JB, Guo L, Rojanasakul Y - PLoS ONE (2012)

Ingenuity Pathways Analysis software output for the downstream components of human Bcl-2-interactome.Twenty molecules of downstream components were reported to date and were labeled in orange, while upstream molecules were labeled in green.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3362580&req=5

pone-0037045-g008: Ingenuity Pathways Analysis software output for the downstream components of human Bcl-2-interactome.Twenty molecules of downstream components were reported to date and were labeled in orange, while upstream molecules were labeled in green.
Mentions: In order to establish a strategy towards a better understanding of the mechanism(s) involved in Bcl-2's contribution to tumorigenesis, we performed an extensive PubMed database search for possible molecular targets. The initial query for Bcl-2 returned 33,970 hits! We realized that other approaches may need to be evaluated given the complexity of Bcl-2 cellular role(s). Following the analysis of available options, we turned to Ingenuity Pathways Analysis (IPA). IPA integrates the primary literature into easily searched and visualized networks allowing for orders of magnitude faster evaluation of cellular signaling cascades. The initial IPA query of Bcl-2's interactions (IPA v8.6) returned 741 hits. In order to make the network more relevant to our model, we filtered for only those interactions reported in humans (Figure 7). This reduced the interaction network to 56 molecules organized by cellular localization (Bcl-2-interactome). Given that we selectively targeted Bcl-2 and observed significant consequences on tumor-associated properties, we asked IPA to map only the downstream components of human Bcl-2-interactome known to date (Figure 8). The query returned 20 molecules. As we progressed from the initial overwhelming complexity of data to the more manageable and relevant Figure 6B, the current mechanistic evidence of Bcl-2's role in tumorigenesis emerged, as did a new approach to scientific query.

Bottom Line: 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.Ingenuity Pathways Analysis (IPA) revealed potential effectors of Bcl-2 in tumorigenesis regulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia, United States of America.

ABSTRACT
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).

Show MeSH
Related in: MedlinePlus