title: Proteomic analysis of pancreatic cancer stem cells: Functional role of fatty acid synthesis and mevalonate pathways.
abstract: Recently, we have shown that the secretome of pancreatic cancer stem cells (CSCs) is characterized by proteins that participate in cancer differentiation, invasion, and metastasis. However, the differentially expressed intracellular proteins that lead to the specific characteristics of pancreatic CSCs have not yet been identified, and as a consequence the deranged metabolic pathways are yet to be elucidated. To identify the modulated proteins of pancreatic CSCs, iTRAQ-based proteomic analysis was performed to compare the proteome of Panc1 CSCs and Panc1 parental cells, identifying 230 modulated proteins. Pathway analysis revealed activation of glycolysis, the pentose phosphate pathway, the pyruvate-malate cycle, and lipid metabolism as well as downregulation of the Krebs cycle, the splicesome and non-homologous end joining. These findings were supported by metabolomics and immunoblotting analysis. It was also found that inhibition of fatty acid synthase by cerulenin and of mevalonate pathways by atorvastatin have a greater anti-proliferative effect on cancer stem cells than parental cells. Taken together, these results clarify some important aspects of the metabolic network signature of pancreatic cancer stem cells, shedding light on key and novel therapeutic targets and suggesting that fatty acid synthesis and mevalonate pathways play a key role in ensuring their viability.
  
  
  
  To better understand the altered metabolic pathways of pancreatic cancer stem cells (CSCs), a comprehensive proteomic analysis and metabolite profiling investigation of Panc1 and Panc1 CSCs were carried out. The findings obtained indicate that Panc1 CSCs are characterized by upregulation of glycolysis, pentose phosphate pathway, pyruvate-malate cycle, and lipid metabolism and by downregulation of Krebs cycle, spliceosome and non-homologous end joining. Moreover, fatty acid synthesis and mevalonate pathways are shown to play a critical contribution to the survival of pancreatic cancer stem cells. This study is helpful for broadening the knowledge of pancreatic cancer stem cells and could accelerate the development of novel therapeutic strategies.
authors.affiliation: University of Verona, Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, Verona 37134, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Brandi
authors.affiliation: University of Verona, Department of Neuroscience, Biomedicine and Movement, Verona 37134, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Dando
authors.affiliation: University of Verona, Department of Neuroscience, Biomedicine and Movement, Verona 37134, Italy.
authors.forename: Elisa Dalla
authors.initials: ED
authors.lastname: Pozza
authors.affiliation: University of Verona, Department of Neuroscience, Biomedicine and Movement, Verona 37134, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Biondani
authors.affiliation: University of Liverpool, MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, Liverpool L69 3GE, United Kingdom.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Jenkins
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Department of Molecular and Therapeutic Cancer Medicine, Royal Liverpool University Hospital, Liverpool L69 3GA, United Kingdom.
authors.forename: Victoria
authors.initials: V
authors.lastname: Elliott
authors.affiliation: University of Liverpool, MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, Liverpool L69 3GE, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Ecological and Biological Sciences, University of Tuscia, Viterbo, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Fanelli
authors.affiliation: Department of Ecological and Biological Sciences, University of Tuscia, Viterbo, Italy.
authors.forename: Lello
authors.initials: L
authors.lastname: Zolla
authors.affiliation: NIHR Liverpool Pancreas Biomedical Research Unit, Department of Molecular and Therapeutic Cancer Medicine, Royal Liverpool University Hospital, Liverpool L69 3GA, United Kingdom.
authors.forename: Eithne
authors.initials: E
authors.lastname: Costello
authors.affiliation: University and Hospital Trust of Verona, Applied Research on Cancer Network (ARC-NET), Department of Pathology and Diagnostics, Verona 37134, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.affiliation: University of Verona, Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, Verona 37134, Italy. Electronic address: daniela.cecconi@univr.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cecconi
authors.affiliation: University of Verona, Department of Neuroscience, Biomedicine and Movement, Verona 37134, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Palmieri
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D064429:Fatty Acid Synthases / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D008798:Mevalonic Acid / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000737:chemistry / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D040901:Proteomics / Q000379:methods*
chemical_list: D005227:Fatty Acids; D064429:Fatty Acid Synthases; D008798:Mevalonic Acid
keywords: Cancer stem cells; Pancreatic cancer; Pancreatic ductal adenocarcinoma PDAC