title: Efavirenz induces autophagy and aberrant differentiation in normal human keratinocytes.
abstract: Although efavirenz (EFV) is efficacious as an antiretroviral therapy when combined with other antiretroviral drugs, it may cause adverse clinical effects, including skin and mucosal eruptions, central nervous system complications, hepatotoxicity, renal failure and pulmonary complications. The present study investigated the phenotypic alterations caused by EFV in normal human keratinocytes (NHKs) and determined the cell death pathways leading to the lack of epithelial proliferation and regeneration. Replication kinetics, cellular morphology, and protein and mRNA levels of cell cycle regulatory genes and cell death markers were compared between the EFV-exposed cells and the untreated control. EFV treatment led to cell proliferation arrest and cell death of the NHKs by inducing autophagy mediated by proteasome-dependent degradation of p53. EFV also reduced the levels of mTOR and active ERK signaling in NHKs. Chemical inhibition of p53 degradation with a proteasome inhibitor led to reduced autophagic response of NHKs to EFV. In addition, EFV triggered terminal differentiation of NHKs by inducing the expression of involucrin, filaggrin, loricrin and genes involved in cornified envelope formation. Inhibition of autophagy in the EFV-treated NHKs with 3-methylalanine reduced the levels of involucrin and the extent of cell death. Our data indicate that EFV elicits cytotoxic effects on NHKs in part through induction of autophagy and aberrant differentiation of cells.
authors.affiliation: School of Dentistry, University of California, Los Angeles, CA, USA.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Dong
authors.forename: Ju-Eun
authors.initials: JE
authors.lastname: Oh
authors.forename: Jin Kyu
authors.initials: JK
authors.lastname: Yi
authors.forename: Reuben H
authors.initials: RH
authors.lastname: Kim
authors.forename: Ki-Hyuk
authors.initials: KH
authors.lastname: Shin
authors.forename: Ronald
authors.initials: R
authors.lastname: Mitsuyasu
authors.forename: No-Hee
authors.initials: NH
authors.lastname: Park
authors.forename: Mo K
authors.initials: MK
authors.lastname: Kang
mesh_terms: D000480:Alkynes; D001343:Autophagy / Q000187:drug effects*; D048588:Benzoxazines / Q000494:pharmacology* / Q000633:toxicity; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003521:Cyclopropanes; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D000091344:Filaggrin Proteins; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D016159:Tumor Suppressor Protein p53; D058570:TOR Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D046988:Proteasome Endopeptidase Complex; C098320:efavirenz
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