title: Ethanol differentially regulates snail family of transcription factors and invasion of premalignant and malignant pancreatic ductal cells.
abstract: Pancreatic cancer is one of the deadliest of cancers with a dismal 5-year survival rate. Epidemiological studies have identified chronic pancreatitis as a risk factor for pancreatic cancer. Pancreatic cancer cells also demonstrate increased expression of the transcription factor Snail, a key regulator of epithelial-mesenchymal transition. As ethanol is one of the major causes of pancreatitis, we examined the effect of ethanol on Snail family members in immortalized human pancreatic ductal epithelial (HPDE) cells and in pancreatic cancer cells. Ethanol induced Snail mRNA levels 2.5-fold in HPDE cells, with only 1.5-fold mRNA induction of the Snail-related protein slug. In contrast, ethanol increased Slug mRNA levels 1.5- to 2-fold in pancreatic cancer cells, with minimal effect on Snail. Because Snail increases invasion of cancer cells, we examined the effect of ethanol on invasion of HPDE and pancreatic cancer cells. Surprisingly, ethanol decreased invasion of HPDE cells, but had no effect on invasion of pancreatic cancer cells. Mechanistically, ethanol increased adhesion of HPDE cells to collagen and increased expression of the collagen binding α2- and β1-integrins. In contrast, ethanol did not affect collagen adhesion or integrin expression in pancreatic cancer cells. Also in contrast to HPDE cells, ethanol did not attenuate ERK1/2 phosphorylation in pancreatic cancer cells; however, inhibiting ERK1/2 decreased pancreatic cancer cell invasion. Overall, our results identify the differential effects of ethanol on premalignant and malignant pancreatic cells, and demonstrate the pleiotropic effects of ethanol on pancreatic cancer progression.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Sarah T
authors.initials: ST
authors.lastname: Ward
authors.forename: Surabhi
authors.initials: S
authors.lastname: Dangi-Garimella
authors.forename: Mario A
authors.initials: MA
authors.lastname: Shields
authors.forename: Brett A
authors.initials: BA
authors.lastname: Collander
authors.forename: Mohammed A Q
authors.initials: MA
authors.lastname: Siddiqui
authors.forename: Seth B
authors.initials: SB
authors.lastname: Krantz
authors.forename: Hidayatullah G
authors.initials: HG
authors.lastname: Munshi
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D000431:Ethanol / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006801:Humans; D039421:Integrin alpha2 / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010183:Pancreatic Ducts / Q000166:cytology*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D039421:Integrin alpha2; D019012:Integrin beta1; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D000431:Ethanol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3