title: Polyploidy Formation in Doxorubicin-Treated Cancer Cells Can Favor Escape from Senescence.
abstract: Cancer cells can undergo stress-induced premature senescence, which is considered to be a desirable outcome of anticancer treatment. However, the escape from senescence and cancer cell repopulation give rise to some doubts concerning the effectiveness of the senescence-induced anticancer therapy. Similarly, it is postulated that polyploidization of cancer cells is connected with disease relapse. We postulate that cancer cell polyploidization associated with senescence is the culprit of atypical cell divisions leading to cancer cell regrowth. Accordingly, we aimed to dissociate between these two phenomena. We induced senescence in HCT 116 cells by pulse treatment with doxorubicin and observed transiently increased ploidy, abnormal nuclear morphology, and various distributions of some proteins (e.g., p21, Ki-67, SA-β-galactosidase) in the subnuclei. Doxorubicin-treated HCT 116 cells displayed an increased production of reactive oxygen species (ROS) possibly caused by an increased amount of mitochondria, which are characterized by low membrane potential. A decrease in the level of ROS by Trolox partially protected the cells from polyploidization but not from senescence. Interestingly, a decreased level of ROS prevented the cells from escaping senescence. We also show that MCF7 cells senesce, but this is not accompanied by the increase of ploidy upon doxorubicin treatment. Moreover, they were stably growth arrested, thus proving that polyploidy but not senescence per se enables to regain the ability to proliferate. Our preliminary results indicate that the different propensity of the HCT 116 and MCF7 cells to increase ploidy upon cell senescence could be caused by a different level of the mTOR and/or Pim-1 kinases.
authors.affiliation: Laboratory of Molecular Bases of Aging, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, 02-093 Poland. Electronic address: g.mosieniak@nencki.gov.pl.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Mosieniak
authors.affiliation: Laboratory of Molecular Bases of Aging, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, 02-093 Poland. Electronic address: m.sliwinska@nencki.gov.pl.
authors.forename: Malgorzata A
authors.initials: MA
authors.lastname: Sliwinska
authors.affiliation: Laboratory of Molecular Bases of Aging, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, 02-093 Poland. Electronic address: o.alster@nencki.gov.pl.
authors.forename: Olga
authors.initials: O
authors.lastname: Alster
authors.affiliation: Laboratory of Molecular Bases of Aging, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, 02-093 Poland. Electronic address: a.strzeszewska@nencki.gov.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Strzeszewska
authors.affiliation: Laboratory of Molecular Bases of Aging, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, 02-093 Poland. Electronic address: p.sunderland@nencki.gov.pl.
authors.forename: Piotr
authors.initials: P
authors.lastname: Sunderland
authors.affiliation: Laboratory of Molecular Bases of Aging, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, 02-093 Poland. Electronic address: m.piechota@nencki.gov.pl.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Piechota
authors.affiliation: Laboratory of Molecular Bases of Aging, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, 02-093 Poland. Electronic address: h.was@nencki.gov.pl.
authors.forename: Halina
authors.initials: H
authors.lastname: Was
authors.affiliation: Laboratory of Molecular Bases of Aging, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, 02-093 Poland. Electronic address: e.sikora@nencki.gov.pl.
authors.forename: Ewa
authors.initials: E
authors.lastname: Sikora
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D002839:Chromans / Q000494:pharmacology; D002869:Chromosome Aberrations / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004317:Doxorubicin / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018613:Microscopy, Confocal; D008855:Microscopy, Electron, Scanning; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011123:Polyploidy; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; C493956:CDKN1A protein, human; D002839:Chromans; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019394:Ki-67 Antigen; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D051573:Proto-Oncogene Proteins c-pim-1; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid