title: Hypoxia-induced modulation of apoptosis and BCL-2 family proteins in different cancer cell types.
abstract: Hypoxia plays an important role in the resistance of tumour cells to chemotherapy. However, the exact mechanisms underlying this process are not well understood. Moreover, according to the cell lines, hypoxia differently influences cell death. The study of the effects of hypoxia on the apoptosis induced by 5 chemotherapeutic drugs in 7 cancer cell types showed that hypoxia generally inhibited the drug-induced apoptosis. In most cases, the effect of hypoxia was the same for all the drugs in one cell type. The expression profile of 93 genes involved in apoptosis as well as the protein level of BCL-2 family proteins were then investigated. In HepG2 cells that are strongly protected against cell death by hypoxia, hypoxia decreased the abundance of nearly all the pro-apoptotic BCL-2 family proteins while none of them are decreased in A549 cells that are not protected against cell death by hypoxia. In HepG2 cells, hypoxia decreased NOXA and BAD abundance and modified the electrophoretic mobility of BIM(EL). BIM and NOXA are important mediators of etoposide-induced cell death in HepG2 cells and the hypoxia-induced modification of these proteins abundance or post-translational modifications partly account for chemoresistance. Finally, the modulation of the abundance and/or of the post-translational modifications of most proteins of the BCL-2 family by hypoxia involves p53-dependent and -independent pathways and is cell type-dependent. A better understanding of these cell-to-cell variations is crucial in order to overcome hypoxia-induced resistance and to ameliorate cancer therapy.
authors.affiliation: Laboratory of Biochemistry and Cellular Biology (URBC), NARILIS, University of Namur - FUNDP, Belgium.
authors.forename: Audrey
authors.initials: A
authors.lastname: Sermeus
authors.forename: Marie
authors.initials: M
authors.lastname: Genin
authors.forename: Amélie
authors.initials: A
authors.lastname: Maincent
authors.forename: Maude
authors.initials: M
authors.lastname: Fransolet
authors.forename: Annick
authors.initials: A
authors.lastname: Notte
authors.forename: Lionel
authors.initials: L
authors.lastname: Leclere
authors.forename: Hélène
authors.initials: H
authors.lastname: Riquier
authors.forename: Thierry
authors.initials: T
authors.lastname: Arnould
authors.forename: Carine
authors.initials: C
authors.lastname: Michiels
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D005047:Etoposide / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D017239:Paclitaxel