Oncotarget

Research Papers:

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

Chandra K. Singh _, Satwinderjeet Kaur, Jasmine George, Minakshi Nihal, Molly C. Pellitteri Hahn, Cameron O. Scarlett and Nihal Ahmad

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Oncotarget. 2015; 6:10335-10349. https://doi.org/10.18632/oncotarget.3231

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Abstract

Chandra K. Singh1,*, Satwinderjeet Kaur1,*, Jasmine George1, Minakshi Nihal1, Molly C. Pellitteri Hahn2, Cameron O. Scarlett2, Nihal Ahmad1,3

1Department of Dermatology, University of Wisconsin, Madison, WI, USA

2School of Pharmacy, University of Wisconsin, Madison, WI, USA

3William S. Middleton VA Medical Center, Madison, WI, USA

*These authors have contributed equally to this work

Correspondence to:

Nihal Ahmad, e-mail: [email protected]

Keywords: pancreatic cancer, sanguinarine, quantitative proteomics, DUSP4, chemoprevention

Received: January 14, 2015     Accepted: January 28, 2015     Published: April 13, 2015

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.


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