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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

Protein-protein interaction by IPA analysisIPA was further used to determine the protein-protein interactions among modulated proteins. The solid lines denote a robust correlation with partner proteins, and dashed lines indicate statistically significant but less frequent correlations. The upregulated proteins upon sanguinarine treatment are represented in red color whereas the downregulated proteins are shown in green. The un-colored nodes indicate additional proteins of this network that were not spotted by the proteomics analysis. The protein-protein interactions are indicated by arrows.
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Figure 4: Protein-protein interaction by IPA analysisIPA was further used to determine the protein-protein interactions among modulated proteins. The solid lines denote a robust correlation with partner proteins, and dashed lines indicate statistically significant but less frequent correlations. The upregulated proteins upon sanguinarine treatment are represented in red color whereas the downregulated proteins are shown in green. The un-colored nodes indicate additional proteins of this network that were not spotted by the proteomics analysis. The protein-protein interactions are indicated by arrows.

Mentions: The protein-protein networks of sanguinarine-modulated proteins were algorithmically generated based on their connectivity. The significance values for network and pathway analyses were computed using Fisher's Exact test. Multiple central nodes, namely L33, ERK, JNK, MAPK, CUL5, GPS1 and DUSP4, were identified from protein-protein networks (Figure 4). However, ERK, JNK and MAPK appeared as additional proteins of this network that were not identified by the proteomics analysis. The protein interaction networks indicated a marked association of DUSP4 in anti-proliferative effects of sanguinarine in pancreatic cancer cells (Figure 4). The protein networks were further systemized through IPA to determine which of the identified proteins are involved in cancer-specific distinct interaction networks. As shown in Supplementary Figure 5, the complex network generated found DUSP4 as an important hub.


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)

Protein-protein interaction by IPA analysisIPA was further used to determine the protein-protein interactions among modulated proteins. The solid lines denote a robust correlation with partner proteins, and dashed lines indicate statistically significant but less frequent correlations. The upregulated proteins upon sanguinarine treatment are represented in red color whereas the downregulated proteins are shown in green. The un-colored nodes indicate additional proteins of this network that were not spotted by the proteomics analysis. The protein-protein interactions are indicated by arrows.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Protein-protein interaction by IPA analysisIPA was further used to determine the protein-protein interactions among modulated proteins. The solid lines denote a robust correlation with partner proteins, and dashed lines indicate statistically significant but less frequent correlations. The upregulated proteins upon sanguinarine treatment are represented in red color whereas the downregulated proteins are shown in green. The un-colored nodes indicate additional proteins of this network that were not spotted by the proteomics analysis. The protein-protein interactions are indicated by arrows.
Mentions: The protein-protein networks of sanguinarine-modulated proteins were algorithmically generated based on their connectivity. The significance values for network and pathway analyses were computed using Fisher's Exact test. Multiple central nodes, namely L33, ERK, JNK, MAPK, CUL5, GPS1 and DUSP4, were identified from protein-protein networks (Figure 4). However, ERK, JNK and MAPK appeared as additional proteins of this network that were not identified by the proteomics analysis. The protein interaction networks indicated a marked association of DUSP4 in anti-proliferative effects of sanguinarine in pancreatic cancer cells (Figure 4). The protein networks were further systemized through IPA to determine which of the identified proteins are involved in cancer-specific distinct interaction networks. As shown in Supplementary Figure 5, the complex network generated found DUSP4 as an important hub.

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