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Molecular signatures of sanguinarine in human pancreatic cancer cells: A large scale label-free comparative proteomics approach.

Singh CK, Kaur S, George J, Nihal M, Pellitteri Hahn MC, Scarlett CO, Ahmad N - Oncotarget (2015)

Bottom Line: Further validation by qRT-PCR and immunoblot analyses demonstrated that the dual specificity phosphatase-4 (DUSP4) was significantly upregulated by sanguinarine in BxPC-3 and MIA PaCa-2 cells.Sanguinarine treatment also caused down-regulation of HIF1α and PCNA, and increased cleavage of PARP and Caspase-7.Taken together, sanguinarine appears to have pleotropic effects, as it modulates multiple key signaling pathways, supporting the potential usefulness of sanguinarine against pancreatic cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University of Wisconsin, Madison, WI, USA.

ABSTRACT
Pancreatic cancer remains one of the most lethal of all human malignancies with its incidence nearly equaling its mortality rate. Therefore, it's crucial to identify newer mechanism-based agents and targets to effectively manage pancreatic cancer. Plant-derived agents/drugs have historically been useful in cancer therapeutics. Sanguinarine is a plant alkaloid with anti-proliferative effects against cancers, including pancreatic cancer. This study was designed to determine the mechanism of sanguinarine's effects in pancreatic cancer with a hope to obtain useful information to improve the therapeutic options for the management of this neoplasm. We employed a quantitative proteomics approach to define the mechanism of sanguinarine's effects in human pancreatic cancer cells. Proteins from control and sanguinarine-treated pancreatic cancer cells were digested with trypsin, run by nano-LC/MS/MS, and identified with the help of Swiss-Prot database. Results from replicate injections were processed with the SIEVE software to identify proteins with differential expression. We identified 37 differentially expressed proteins (from a total of 3107), which are known to be involved in variety of cellular processes. Four of these proteins (IL33, CUL5, GPS1 and DUSP4) appear to occupy regulatory nodes in key pathways. Further validation by qRT-PCR and immunoblot analyses demonstrated that the dual specificity phosphatase-4 (DUSP4) was significantly upregulated by sanguinarine in BxPC-3 and MIA PaCa-2 cells. Sanguinarine treatment also caused down-regulation of HIF1α and PCNA, and increased cleavage of PARP and Caspase-7. Taken together, sanguinarine appears to have pleotropic effects, as it modulates multiple key signaling pathways, supporting the potential usefulness of sanguinarine against pancreatic cancer.

No MeSH data available.


Related in: MedlinePlus

Gene ontology analysis of proteome changesIdentified proteins showing > 1.8 fold change were systematized on the basis of (A) molecular functions, (B) biological processes and (C) protein classes, by PANTHER classification system.
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Figure 2: Gene ontology analysis of proteome changesIdentified proteins showing > 1.8 fold change were systematized on the basis of (A) molecular functions, (B) biological processes and (C) protein classes, by PANTHER classification system.

Mentions: To better understand the biological pathways being affected by modulation of protein abundance in response to sanguinarine, the selected 37 proteins were annotated with gene ontology (GO) terms using Protein ANnalysis THrough Evolutionary Relationships (PANTHER) classification system. The distribution of these proteins among molecular functions, biological processes and protein classes are illustrated in Figure 2. It is noteworthy that most of the differentially regulated proteins are involved in binding and catalytic activity, followed by lesser involvement of enzyme regulator, nucleic acid binding transcription factor, receptor, structural molecule and transporter activity (Figure 2A). The GO analysis on the basis of biological processes, which show the molecular events pertinent to the functioning of integrated living system, explored the majorly involvement of proteins related with metabolic and cellular processes (Figure 2B). Sanguinarine also modulate biological regulation, developmental process, localization, cellular component organization, multicellular organismal, response to stimulus, immune system, reproduction and apoptotic processes. The protein class analysis shows the pleotropic mode of action of sanguinarine as it affects broad category of protein classes namely chaperones, transcription factors, hydrolase, signaling molecules, ligase, enzyme modulators, transporter, transferase, receptor, cytoskeletal protein, nucleic acid binding, protease, phosphatase, membrane traffic protein and kinase (Figure 2C). Taken together, the data from gene ontology suggest that sanguinarine affects multiple critical cellular processes that are relevant to cell growth and proliferation.


Molecular signatures of sanguinarine in human pancreatic cancer cells: A large scale label-free comparative proteomics approach.

Singh CK, Kaur S, George J, Nihal M, Pellitteri Hahn MC, Scarlett CO, Ahmad N - Oncotarget (2015)

Gene ontology analysis of proteome changesIdentified proteins showing > 1.8 fold change were systematized on the basis of (A) molecular functions, (B) biological processes and (C) protein classes, by PANTHER classification system.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496359&req=5

Figure 2: Gene ontology analysis of proteome changesIdentified proteins showing > 1.8 fold change were systematized on the basis of (A) molecular functions, (B) biological processes and (C) protein classes, by PANTHER classification system.
Mentions: To better understand the biological pathways being affected by modulation of protein abundance in response to sanguinarine, the selected 37 proteins were annotated with gene ontology (GO) terms using Protein ANnalysis THrough Evolutionary Relationships (PANTHER) classification system. The distribution of these proteins among molecular functions, biological processes and protein classes are illustrated in Figure 2. It is noteworthy that most of the differentially regulated proteins are involved in binding and catalytic activity, followed by lesser involvement of enzyme regulator, nucleic acid binding transcription factor, receptor, structural molecule and transporter activity (Figure 2A). The GO analysis on the basis of biological processes, which show the molecular events pertinent to the functioning of integrated living system, explored the majorly involvement of proteins related with metabolic and cellular processes (Figure 2B). Sanguinarine also modulate biological regulation, developmental process, localization, cellular component organization, multicellular organismal, response to stimulus, immune system, reproduction and apoptotic processes. The protein class analysis shows the pleotropic mode of action of sanguinarine as it affects broad category of protein classes namely chaperones, transcription factors, hydrolase, signaling molecules, ligase, enzyme modulators, transporter, transferase, receptor, cytoskeletal protein, nucleic acid binding, protease, phosphatase, membrane traffic protein and kinase (Figure 2C). Taken together, the data from gene ontology suggest that sanguinarine affects multiple critical cellular processes that are relevant to cell growth and proliferation.

Bottom Line: Further validation by qRT-PCR and immunoblot analyses demonstrated that the dual specificity phosphatase-4 (DUSP4) was significantly upregulated by sanguinarine in BxPC-3 and MIA PaCa-2 cells.Sanguinarine treatment also caused down-regulation of HIF1α and PCNA, and increased cleavage of PARP and Caspase-7.Taken together, sanguinarine appears to have pleotropic effects, as it modulates multiple key signaling pathways, supporting the potential usefulness of sanguinarine against pancreatic cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University of Wisconsin, Madison, WI, USA.

ABSTRACT
Pancreatic cancer remains one of the most lethal of all human malignancies with its incidence nearly equaling its mortality rate. Therefore, it's crucial to identify newer mechanism-based agents and targets to effectively manage pancreatic cancer. Plant-derived agents/drugs have historically been useful in cancer therapeutics. Sanguinarine is a plant alkaloid with anti-proliferative effects against cancers, including pancreatic cancer. This study was designed to determine the mechanism of sanguinarine's effects in pancreatic cancer with a hope to obtain useful information to improve the therapeutic options for the management of this neoplasm. We employed a quantitative proteomics approach to define the mechanism of sanguinarine's effects in human pancreatic cancer cells. Proteins from control and sanguinarine-treated pancreatic cancer cells were digested with trypsin, run by nano-LC/MS/MS, and identified with the help of Swiss-Prot database. Results from replicate injections were processed with the SIEVE software to identify proteins with differential expression. We identified 37 differentially expressed proteins (from a total of 3107), which are known to be involved in variety of cellular processes. Four of these proteins (IL33, CUL5, GPS1 and DUSP4) appear to occupy regulatory nodes in key pathways. Further validation by qRT-PCR and immunoblot analyses demonstrated that the dual specificity phosphatase-4 (DUSP4) was significantly upregulated by sanguinarine in BxPC-3 and MIA PaCa-2 cells. Sanguinarine treatment also caused down-regulation of HIF1α and PCNA, and increased cleavage of PARP and Caspase-7. Taken together, sanguinarine appears to have pleotropic effects, as it modulates multiple key signaling pathways, supporting the potential usefulness of sanguinarine against pancreatic cancer.

No MeSH data available.


Related in: MedlinePlus