title: BNIP3 protects HepG2 cells against etoposide-induced cell death under hypoxia by an autophagy-independent pathway.
abstract: Tumor hypoxia is a common characteristic of most solid tumors and is correlated with poor prognosis for patients partly because hypoxia promotes resistance to cancer therapy. Hypoxia selects cancer cells that are resistant to apoptosis and allows the onset of mechanisms that promote cancer cells survival including autophagy. Previously, we showed that human hepatoma HepG2 cells were protected under hypoxia against the etoposide-induced apoptosis. In this study, respective putative contribution of autophagy and BNIP3 in the protection conferred by hypoxia against the etoposide-induced apoptosis was investigated. We report that autophagy is induced by etoposide, a process that is not affected by hypoxic conditions. Using Atg5 siRNA, we show that etoposide-induced autophagy promotes apoptotic cell death under normoxia but not under hypoxia. Then, we investigated whether the hypoxia-induced protein BNIP3 could explain the different effect of autophagy on cell death under hypoxia or normoxia. We show that the silencing of BNIP3 does not affect autophagy whatever the pO(2) but participates in the protective effect of hypoxia against etoposide-induced apoptosis. Together, these results suggest that autophagy might be involved in etoposide-induced cell death only under normoxia and that BNIP3 is a major effector of the protective mechanism conferred by hypoxia to protect cancer cells against etoposide-induced apoptotic cell death.
authors.affiliation: Laboratory of Biochemistry and Cellular Biology (URBC), NAmur Research Institute for LIfe Science (NARILIS), FUNDP-University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Cosse
authors.forename: Guillaume
authors.initials: G
authors.lastname: Rommelaere
authors.forename: Noelle
authors.initials: N
authors.lastname: Ninane
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*; D001343:Autophagy / Q000502:physiology*; D015687:Cell Hypoxia / Q000502:physiology*; D005047:Etoposide / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010101:Oxygen Consumption; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D014617:Vacuoles
chemical_list: D000970:Antineoplastic Agents; C090121:BNIP3 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D005047:Etoposide