title: Withaferin A suppresses the up-regulation of acetyl-coA carboxylase 1 and skin tumor formation in a skin carcinogenesis mouse model.
abstract: Withaferin A (WA), a natural product derived from Withania somnifera, has been used in traditional oriental medicines to treat neurological disorders. Recent studies have demonstrated that this compound may have a potential for cancer treatment and a clinical trial has been launched to test WA in treating melanoma. Herein, WA's chemopreventive potential was tested in a chemically-induced skin carcinogenesis mouse model. Pathological examinations revealed that WA significantly suppressed skin tumor formation. Morphological observations of the skin tissues suggest that WA suppressed cell proliferation rather than inducing apoptosis during skin carcinogenesis. Antibody Micro array analysis demonstrated that WA blocked carcinogen-induced up-regulation of acetyl-CoA carboxylase 1 (ACC1), which was further confirmed in a skin cell transformation model. Overexpression of ACC1 promoted whereas knockdown of ACC1 suppressed anchorage-independent growth and oncogene activation of transformable skin cells. Further studies demonstrated that WA inhibited tumor promotor-induced ACC1 gene transcription by suppressing the activation of activator protein 1. In melanoma cells, WA was also able to suppress the expression levels of ACC1. Finally, results using human skin cancer tissues confirmed the up-regulation of ACC1 in tumors than adjacent normal tissues. In summary, our results suggest that withaferin A may have a potential in chemoprevention and ACC1 may serve as a critical target of WA. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, USA.|Department of Basic Medicine, Heibei University, Baoding, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, USA.|Department of Basic Medicine, Qiqihar Medical University, Qiqihar, China.
authors.forename: Chunjing
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, USA.|College of Biotechnology, Southern Medical University, Guangzhou, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Du
authors.affiliation: Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, USA.
authors.forename: Brandi
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Harris
authors.affiliation: Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, USA.
authors.forename: Quitin
authors.initials: Q
authors.lastname: Richardson
authors.affiliation: Department of Pathology, LSU Health Sciences Center in Shreveport, Shreveport, USA.
authors.forename: Xinggui
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Neurosurgery, LSU Health Sciences Center in Shreveport, Shreveport, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Jin
authors.affiliation: Department of Neurosurgery, LSU Health Sciences Center in Shreveport, Shreveport, USA.
authors.forename: Guohong
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Pathology, LSU Health Sciences Center in Shreveport, Shreveport, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Kevil
authors.affiliation: Department of Pathology, LSU Health Sciences Center in Shreveport, Shreveport, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Gu
authors.affiliation: Feist-Weiller Cancer Center, LSU Health Sciences Center in Shreveport, Shreveport, USA.
authors.forename: Runhua
authors.initials: R
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, Toxicology and Neuroscience, LSU Health Sciences Center in Shreveport, Shreveport, USA. yzhao1@lsuhsc.edu.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D012878:Skin Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects*; D054358:Withanolides / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D018808:Transcription Factor AP-1; D054358:Withanolides; C000616953:ACC1 protein, mouse; D000103:Acetyl-CoA Carboxylase; C009684:withaferin A
keywords: ACC1; apoptosis; cell proliferation; skin carcinogenesis; withaferin A