title: Dehydroepiandrosterone triggers autophagic cell death in human hepatoma cell line HepG2 via JNK-mediated p62/SQSTM1 expression.
abstract: Autophagy is a catabolic process that cancer cells usually exploit during stress conditions to provide energy by recycling organelles and proteins. Beyond its prosurvival role, it is well accepted that occurrence of autophagy is often associated with a particular type of programmed cell death known as autophagic cell death (ACD). Dehydroepiandrosterone (DHEA) is an endogenous hormone showing anticancer properties even if the underlying mechanisms are not fully clear yet. Here, we provide evidence that DHEA induces ACD in human hepatoma cell line, HepG2. Indeed, autophagy inhibitors (i.e. 3-methyladenine or Atg5 siRNA) significantly reduced the percentage of dead cells. DHEA induces p62-dependent autophagy, which turns detrimental and brings about death. DHEA stimulates reactive oxygen species-independent jun N-terminal kinase (JNK) phosphoactivation and the treatment with JNK inhibitor reduces p62 mRNA levels, as well as DHEA-induced ACD. The transcription factor nuclear factor (erythroid-derived-2)-like-2 (Nrf2) constitutes the link between JNK and p62 since its migration to the nucleus is suppressed by JNK inhibitor and its inhibition through a dominant negative Nrf2 plasmid transfection decreases p62 protein levels. Overall, our data indicate that DHEA induces ACD in HepG2 via a JNK-Nrf2-p62 axis. Thus, DHEA could represent a new appealing drug for eliminating tumor cells through autophagy particularly in apoptosis-resistant cases.
authors.affiliation: Department of Biology, University of Rome 'Tor Vergata', Rome 00133, Italy and.
authors.forename: Rolando
authors.initials: R
authors.lastname: Vegliante
authors.affiliation: Department of Biology, University of Rome 'Tor Vergata', Rome 00133, Italy and Present address: Department of Microbiology, Immunobiology and Genetics, University of Vienna, Vienna 1030, Austria.
authors.forename: Enrico
authors.initials: E
authors.lastname: Desideri
authors.affiliation: Department of Biology, University of Rome 'Tor Vergata', Rome 00133, Italy and.
authors.forename: Luca
authors.initials: L
authors.lastname: Di Leo
authors.affiliation: Department of Biology, University of Rome 'Tor Vergata', Rome 00133, Italy and IRCCS San Raffaele, Rome 00166, Italy ciriolo@bio.uniroma2.it.
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Ciriolo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D002277:Carcinoma / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000096:biosynthesis; D060888:Real-Time Polymerase Chain Reaction; D000071456:Sequestosome-1 Protein; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C118585:P62 protein, human; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D003687:Dehydroepiandrosterone; D048670:MAP Kinase Kinase 4