title: Ergosterol peroxide activates Foxo3-mediated cell death signaling by inhibiting AKT and c-Myc in human hepatocellular carcinoma cells.
abstract: Sterols are the important active ingredients of fungal secondary metabolites to induce death of tumor cells. In our previous study, we found that ergosterol peroxide (5α, 8α-epidioxiergosta-6, 22-dien-3β-ol), purified from Ganoderma lucidum, induced human cancer cell death. Since the amount of purified ergosterol peroxide is not sufficient to perform in vivo experiments or apply clinically, we developed an approach to synthesize ergosterol peroxide chemically. After confirming the production of ergosterol peroxide, we examined the biological functions of the synthetic ergosterol peroxide. The results showed that ergosterol peroxide induced cell death and inhibited cell migration, cell cycle progression, and colony growth of human hepatocellular carcinoma cells. We further examined the mechanism associated with this effect and found that treatment with ergosterol peroxide increased the expression of Foxo3 mRNA and protein in HepG2 cells. The upstream signal proteins pAKT and c-Myc, which can inhibit Foxo3 functions, were clearly decreased in HepG2 cells treated with ergosterol peroxide. The levels of Puma and Bax, pro-apoptotic proteins, were effectively enhanced. Our results suggest that ergosterol peroxide stimulated Foxo3 activity by inhibiting pAKT and c-Myc and activating pro-apoptotic protein Puma and Bax to induce cancer cell death.
authors.affiliation: State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Institute of Microbiology, Guangzhou, PR China.|Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
authors.forename: Xiangmin
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Institute of Microbiology, Guangzhou, PR China.
authors.forename: Qingping
authors.initials: Q
authors.lastname: Wu
authors.affiliation: College of Life Science and Bioengineering, Beijing University of Technology, Pingleyuan, Chaoyang, Beijing, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Bu
authors.affiliation: College of Life Science and Bioengineering, Beijing University of Technology, Pingleyuan, Chaoyang, Beijing, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Hu
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
authors.forename: William W
authors.initials: WW
authors.lastname: Du
authors.affiliation: State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Institute of Microbiology, Guangzhou, PR China.|Guangdong Yuewei Edible Fungi Technology Co. Ltd, Guangzhou, China.
authors.forename: Chunwei
authors.initials: C
authors.lastname: Jiao
authors.affiliation: State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Institute of Microbiology, Guangzhou, PR China.
authors.forename: Honghui
authors.initials: H
authors.lastname: Pan
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
authors.forename: Mouna
authors.initials: M
authors.lastname: Sdiri
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
authors.forename: Nan
authors.initials: N
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Institute of Microbiology, Guangzhou, PR China.|Guangdong Yuewei Edible Fungi Technology Co. Ltd, Guangzhou, China.
authors.forename: Yizhen
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.|Institute of Medical Science, University of Toronto, Toronto, Canada.
authors.forename: Burton B
authors.initials: BB
authors.lastname: Yang
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004875:Ergosterol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C438378:BBC3 protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; C489427:MYC protein, human; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D051028:bcl-2-Associated X Protein; D051057:Proto-Oncogene Proteins c-akt; C036071:ergosterol-5,8-peroxide; D004875:Ergosterol
keywords: Foxo3; Puma; c-Myc; ergosterol peroxide; pAKT