title: Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer.
abstract: Cancer cells are known to execute reprogramed metabolism of glucose, amino acids and lipids. Here, we report a significant role of cholesterol metabolism in cancer metastasis. By using label-free Raman spectromicroscopy, we found an aberrant accumulation of cholesteryl ester in human pancreatic cancer specimens and cell lines, mediated by acyl-CoA cholesterol acyltransferase-1 (ACAT-1) enzyme. Expression of ACAT-1 showed a correlation with poor patient survival. Abrogation of cholesterol esterification, either by an ACAT-1 inhibitor or by shRNA knockdown, significantly suppressed tumor growth and metastasis in an orthotopic mouse model of pancreatic cancer. Mechanically, ACAT-1 inhibition increased intracellular free cholesterol level, which was associated with elevated endoplasmic reticulum stress and caused apoptosis. Collectively, our results demonstrate a new strategy for treating metastatic pancreatic cancer by inhibiting cholesterol esterification.
authors.affiliation: Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Wells Center for Pediatric Research, IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Gu
authors.affiliation: Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA.
authors.forename: S S-Y
authors.initials: SS
authors.lastname: Lee
authors.affiliation: Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA.
authors.forename: B
authors.initials: B
authors.lastname: Song
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bandyopadhyay
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.|Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
authors.forename: S F
authors.initials: SF
authors.lastname: Konieczny
authors.affiliation: Center for Cancer Research, Purdue University, West Lafayette, IN, USA.|Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Ratliff
authors.affiliation: Center for Cancer Research, Purdue University, West Lafayette, IN, USA.|Department of Biochemistry, Purdue University, West Lafayette, IN, USA.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Wells Center for Pediatric Research, IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Xie
authors.affiliation: Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA.|Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
authors.forename: J-X
authors.initials: JX
authors.lastname: Cheng
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002788:Cholesterol Esters / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D004951:Esterification; D006801:Humans; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D051059:PTEN Phosphohydrolase / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D002788:Cholesterol Esters; C506639:ACAT1 protein, human; D000101:Acetyl-CoA C-Acetyltransferase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human