title: Role of stress-activated OCT4A in the cell fate decisions of embryonal carcinoma cells treated with etoposide.
abstract: Tumor cellular senescence induced by genotoxic treatments has recently been found to be paradoxically linked to the induction of "stemness." This observation is critical as it directly impinges upon the response of tumors to current chemo-radio-therapy treatment regimens. Previously, we showed that following etoposide (ETO) treatment embryonal carcinoma PA-1 cells undergo a p53-dependent upregulation of OCT4A and p21Cip1 (governing self-renewal and regulating cell cycle inhibition and senescence, respectively). Here we report further detail on the relationship between these and other critical cell-fate regulators. PA-1 cells treated with ETO display highly heterogeneous increases in OCT4A and p21Cip1 indicative of dis-adaptation catastrophe. Silencing OCT4A suppresses p21Cip1, changes cell cycle regulation and subsequently suppresses terminal senescence; p21Cip1-silencing did not affect OCT4A expression or cellular phenotype. SOX2 and NANOG expression did not change following ETO treatment suggesting a dissociation of OCT4A from its pluripotency function. Instead, ETO-induced OCT4A was concomitant with activation of AMPK, a key component of metabolic stress and autophagy regulation. p16ink4a, the inducer of terminal senescence, underwent autophagic sequestration in the cytoplasm of ETO-treated cells, allowing alternative cell fates. Accordingly, failure of autophagy was accompanied by an accumulation of p16ink4a, nuclear disintegration, and loss of cell recovery. Together, these findings imply that OCT4A induction following DNA damage in PA-1 cells, performs a cell stress, rather than self-renewal, function by moderating the expression of p21Cip1, which alongside AMPK helps to then regulate autophagy. Moreover, this data indicates that exhaustion of autophagy, through persistent DNA damage, is the cause of terminal cellular senescence.
authors.affiliation: a Latvian Biomedical Research and Study Center ; Riga, Latvia.
authors.forename: Anda
authors.initials: A
authors.lastname: Huna
authors.affiliation: a Latvian Biomedical Research and Study Center ; Riga, Latvia.
authors.forename: Kristine
authors.initials: K
authors.lastname: Salmina
authors.affiliation: a Latvian Biomedical Research and Study Center ; Riga, Latvia.
authors.forename: Jekaterina
authors.initials: J
authors.lastname: Erenpreisa
authors.affiliation: a Latvian Biomedical Research and Study Center ; Riga, Latvia.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Vazquez-Martin
authors.affiliation: a Latvian Biomedical Research and Study Center ; Riga, Latvia.
authors.forename: Jekabs
authors.initials: J
authors.lastname: Krigerts
authors.affiliation: a Latvian Biomedical Research and Study Center ; Riga, Latvia.
authors.forename: Inna
authors.initials: I
authors.lastname: Inashkina
authors.affiliation: a Latvian Biomedical Research and Study Center ; Riga, Latvia.|d R. E. Kavetsky Institute of Experimental Pathology; Oncology and Radiobiology; National Academy of Sciences of Ukraine ; Kyiv , Ukraine.
authors.forename: Bogdan I
authors.initials: BI
authors.lastname: Gerashchenko
authors.affiliation: b Institute of Cancer Sciences; Manchester Cancer Research Center; University of Manchester; Manchester Academic Health Science Center ; Manchester , UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Townsend
authors.affiliation: c Cancer Sciences Unit; University of Southampton; Faculty of Medicine; General Hospital ; Southampton , UK.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cragg
authors.affiliation: b Institute of Cancer Sciences; Manchester Cancer Research Center; University of Manchester; Manchester Academic Health Science Center ; Manchester , UK.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Jackson
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D001343:Autophagy / Q000187:drug effects; D059447:Cell Cycle Checkpoints; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000378:metabolism / Q000502:physiology*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D005047:Etoposide; D055372:AMP-Activated Protein Kinases
keywords: DNA damage; OCT4A/POU5F1; cell-fate; p16ink4a; p21Cip1; p53; p62; pluripotency; self-renewal; senescence; tumor cells