title: Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness.
abstract: Altered lipid metabolism is increasingly recognized as a signature of cancer cells. Enabled by label-free Raman spectromicroscopy, we performed quantitative analysis of lipogenesis at single-cell level in human patient cancerous tissues. Our imaging data revealed an unexpected, aberrant accumulation of esterified cholesterol in lipid droplets of high-grade prostate cancer and metastases. Biochemical study showed that such cholesteryl ester accumulation was a consequence of loss of tumor suppressor PTEN and subsequent activation of PI3K/AKT pathway in prostate cancer cells. Furthermore, we found that such accumulation arose from significantly enhanced uptake of exogenous lipoproteins and required cholesterol esterification. Depletion of cholesteryl ester storage significantly reduced cancer proliferation, impaired cancer invasion capability, and suppressed tumor growth in mouse xenograft models with negligible toxicity. These findings open opportunities for diagnosing and treating prostate cancer by targeting the altered cholesterol metabolism.
authors.affiliation: Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Shuhua
authors.initials: S
authors.lastname: Yue
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Junjie
authors.initials: J
authors.lastname: Li
authors.affiliation: Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Seung-Young
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Hyeon Jeong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Shao
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Song
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Urology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Masterson
authors.affiliation: Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA; Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA; Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Ratliff
authors.affiliation: Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA; Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA. Electronic address: jcheng@purdue.edu.
authors.forename: Ji-Xin
authors.initials: JX
authors.lastname: Cheng
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D002788:Cholesterol Esters / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D002788:Cholesterol Esters; D011944:Receptors, Androgen; D011973:Receptors, LDL; D002784:Cholesterol; C506639:ACAT1 protein, human; D000101:Acetyl-CoA C-Acetyltransferase; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human