title: Stress induced premature senescence: a new culprit in ovarian tumorigenesis?
abstract: Stress induced premature senescence (SIPS) is a relative extension to the concept of exogenous cellular insult. Besides persistent double strand (ds) DNA breaks and increased β-galactosidase activity, biological significance of telomeric attrition in conjunction with senescence associated secretory phenotype (SASP) has been highlighted in SIPS. To gain insight on the potential role of this unique phenomenon invoked upon environmental stress, we sequentially validated the molecular repercussions of this event in ovarian epithelial cells after exposure to methyl isocyanate, an elegant regulator of cellular biotransformation. Persistent accumulation of DNA damage response factors phospho-ATM/γ-H2AX, morphological changes with increased cell size and early yet incremental β-gal staining, imply the inception of premature senescence. Advent of SASP is attributed by prolonged secretion of pro-inflammatory cytokines along with untimely but significant G1/S cell cycle arrest. Telomeric dysfunction associated with premature senescence is indicative of early loss of TRF2 (telomeric repeat binding factor 2) protein and resultant multiple translocations. Induction of senescence-associated heterochromatic foci formation showcases the chromatin alterations in form of trimethylated H3K9me3 in conjunction with H4 hypoacetylation and altered miRNA expression. Anchorage-independent neoplastic growth observed in treated cells reaffirms the oncogenic transformation following the exposure. Collectively, we infer the possible role of SIPS, as a central phenomenon, to perturbed genomic integrity in ovarian surface epithelium, orchestrated through SASP and chromatin level alterations, a hitherto unknown molecular paradigm. Although translational utility of SIPS as a biomarker for estimating ovarian cancer risk seems evident, further investigations will be imperative to provide a tangible way for its precise validation in clinical settings.
authors: Gorantla Venkata
authors: GV
authors: Raghuram
authors: Division of Translational Research, Tata Memorial Centre, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Navi Mumbai, India.
authors: Pradyumna Kumar
authors: PK
authors: Mishra
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D063646:Carcinogenesis / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D016922:Cellular Senescence / Q000502:physiology*; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D017953:Isocyanates / Q000009:adverse effects; D010051:Ovarian Neoplasms / Q000209:etiology*; D010053:Ovary / Q000166:cytology; D013312:Stress, Physiological / Q000502:physiology*; D059506:Telomere Shortening / Q000502:physiology*; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism
chemical_list: D015415:Biomarkers; C468783:H2AX protein, human; D006657:Histones; D017953:Isocyanates; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2; C008461:methyl isocyanate