title: 4-cholesten-3-one suppresses lung adenocarcinoma metastasis by regulating translocation of HMGB1, HIF1α and Caveolin-1.
abstract: Metastasis is a great challenge in lung adenocarcinoma (ADC) therapy. Cholesterol has been implicated in ADC metastasis. 4-cholesten-3-one, as cholesterol metabolite and analog, can substitute membrane cholesterol and increase membrane fluidity. In this study, we explored the possibility that 4-cholesten-3-one inhibited ADC metastasis. Low-dose 4-cholesten-3-one significantly restrained ADC cells migration and invasion with little effects on cells viabilities. Further investigation showed that 4-cholesten-3-one promoted ROS generation, which transiently activated AMPKα1, increased HIF1α expression, reduced Bcl-2 expression and caused autophagy. AMPKα1 knockdown partly suppressed 4-cholesten-3-one-induced autophagy but, neither prevented 4-cholesten-3-one-induced upregulation of HIF1α or downregulation of Bcl-2. 4-cholesten-3-one-induced autophagy facilitated the release of HMGB1 from nuclei to cytoplasm, blocking nuclear translocation of HIF1α and activation of MMP2 and MMP9. Also, 4-cholesten-3-one induced time-dependent phosphorylation of caveolin-1, Akt and NF-κB. With increasing treatment time, 4-cholesten-3-one accelerated caveolin-1 internalization, but reduced the phosphorylation of Akt and NF-κB, and inhibited the expression of snail and twist. These data suggested that 4-cholesten-3-one could be a potential candidate for anti-metastasis of lung adenocarcinoma.
authors.affiliation: Department of Anesthesiology, Shandong provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Jinben
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Oncology, Shandong provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Guobin
authors.initials: G
authors.lastname: Fu
authors.affiliation: Department of Anesthesiology, Shandong provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of thoracic surgery, Shandong chest Hospital, Jinan 250021, China.
authors.forename: Shaoxian
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Hand and Foot Surgery, Shandong provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Lishan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Ultrasound, Shandong provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Ultrasound, Shandong provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Anesthesiology, Shandong provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Mengyuan
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Center Laboratory, Shandong provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Yanliang
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of burn and plastic surgery, Shandong provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Yibing
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D000077192:Adenocarcinoma of Lung; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001932:Brain Neoplasms / Q000556:secondary; D051242:Caveolin 1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002783:Cholestenones / Q000494:pharmacology / Q000627:therapeutic use*; D002784:Cholesterol / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D024243:HMGB1 Protein / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051242:Caveolin 1; D002783:Cholestenones; D024243:HMGB1 Protein; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; C000475:cholest-4-en-3-one; D002784:Cholesterol