Open AccessJournal Article
A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents
Bey-Dih Chang,Eugenia V. Broude,Milos Dokmanovic,Hongming Zhu,Adam Ruth,Yongzhi Xuan,Eugene S. Kandel,Ekkehart Lausch,Konstantin Christov,Igor B. Roninson +9 more
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TLDR
SLP induction in breast carcinoma cells treated with retinoids in vitro or in vivo was found to correlate with permanent growth inhibition under the conditions of minimal cytotoxicity, suggesting that this response may be particularly important for the antiproliferative effect of differentiating agents.Abstract:
Exposure of human tumor cell lines to different chemotherapeutic drugs, ionizing radiation, and differentiating agents induced morphological, enzymatic, and ploidy changes resembling replicative senescence of normal cells. Moderate doses of doxorubicin induced this senescence-like phenotype (SLP) in 11 of 14 tested cell lines derived from different types of human solid tumors, including all of the lines with wild-type p53 and half of p53-mutated cell lines. SLP induction seemed to be independent from mitotic cell death, the other major effect of drug treatment. Among cells that survived drug exposure, SLP markers distinguished those cells that became terminally growth-arrested within a small number of cell divisions from the cells that recovered and resumed proliferation. SLP induction in breast carcinoma cells treated with retinoids in vitro or in vivo was found to correlate with permanent growth inhibition under the conditions of minimal cytotoxicity, suggesting that this response may be particularly important for the antiproliferative effect of differentiating agents. The senescence-like program of terminal proliferation arrest may provide an important determinant of treatment outcome and a target for augmentation in cancer therapy.read more
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Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence.
Masashi Narita,Sabrina Nuñez,Sabrina Nuñez,Edith Heard,Masako Narita,Athena W. Lin,Stephen Hearn,David L. Spector,Gregory J. Hannon,Scott W. Lowe +9 more
TL;DR: A distinct heterochromatic structure that accumulates in senescent human fibroblasts is described, which is designated senescence-associated heterochROMatic foci (SAHF) and is associated with the stable repression of E2F target genes.
Journal ArticleDOI
Apoptosis in cancer
Scott W. Lowe,Athena W. Lin +1 more
TL;DR: An intense research effort is uncovering the underlying mechanisms of apoptosis such that, in the next decade, one envisions that this information will produce new strategies to exploit apoptosis for therapeutic benefit.
Journal ArticleDOI
Oncogene-induced senescence as an initial barrier in lymphoma development
Melanie Braig,Soyoung Lee,Christoph Loddenkemper,Cornelia Rudolph,Antoine H.F.M. Peters,Antoine H.F.M. Peters,Brigitte Schlegelberger,Harald Stein,Bernd Dörken,Bernd Dörken,Thomas Jenuwein,Clemens A. Schmitt,Clemens A. Schmitt +12 more
TL;DR: H3K9me-mediated senescence is identified as a novel Suv39h1-dependent tumour suppressor mechanism whose inactivation permits the formation of aggressive but apoptosis-competent lymphomas in response to oncogenic Ras.
Journal ArticleDOI
A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy.
Clemens A. Schmitt,Jordan S. Fridman,Meng Yang,Soyoung Lee,Eugene Baranov,Robert M. Hoffman,Scott W. Lowe +6 more
TL;DR: It is shown that primary murine lymphomas also respond to chemotherapy by engaging a senescence program controlled by p53 and p16(INK4a), and mice bearing tumors capable of drug-induced senescENCE have a much better prognosis following chemotherapy than those harboring tumors with senescences defects.
Journal ArticleDOI
MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation
Remi-Martin Laberge,Yu Sun,Arturo V. Orjalo,Christopher K. Patil,Adam Freund,Lili Zhou,Samuel C. Curran,Albert R. Davalos,Kathleen A. Wilson-Edell,Su Liu,Chandani Limbad,Marco Demaria,Patrick Wai-Lun Li,Gene B. Hubbard,Yuji Ikeno,Martin A. Javors,Pierre Yves Desprez,Christopher C. Benz,Pankaj Kapahi,Peter S. Nelson,Judith Campisi +20 more
TL;DR: It is shown that rapamycin selectively blunts the pro-inflammatory phenotype of senescent cells, which might ameliorate age-related pathologies, including late-life cancer, by suppressing senescence-associated inflammation.
References
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Journal ArticleDOI
Requirement for p53 and p21 to Sustain G2 Arrest After DNA Damage
Fred Bunz,A. Dutriaux,Christoph Lengauer,Todd Waldman,Shibin Zhou,J. P. Brown,John M. Sedivy,Kenneth W. Kinzler,Bert Vogelstein +8 more
TL;DR: After DNA damage, many cells appear to enter a sustained arrest in the G2 phase of the cell cycle but this arrest could be sustained only when p53 was present in the cell and capable of transcriptionally activating the cyclin-dependent kinase inhibitor p21.