title: Bafilomycin A1 triggers proliferative potential of senescent cancer cells in vitro and in NOD/SCID mice.
abstract: Anticancer therapies that induce DNA damage tend to trigger senescence in cancer cells, a process known as therapy-induced senescence (TIS). Such cells may undergo atypical divisions, thus contributing to tumor re-growth. Accumulation of senescent cancer cells reduces survival of patients after chemotherapy. As senescence interplays with autophagy, a dynamic recycling process, we sought to study whether inhibition of autophagy interferes with divisions of TIS cells. We exposed human colon cancer HCT116 cells to repeated cycles of a chemotherapeutic agent - doxorubicin (doxo) and demonstrated induction of hallmarks of TIS (e.g. growth arrest, hypertrophy, poliploidization and secretory phenotype) and certain properties of cancer stem cells (increased NANOG expression, percentages of CD24+ cells and side population). Colonies of small and highly proliferative progeny appeared shortly after drug removal. Treatment with bafilomycin A1 (BAF A1), an autophagy inhibitor, postponed short term in vitro cell re-population. It was associated with reduction in the number of diploid and increase in the number of poliploid cells. In a long term, a pulse of BAF A1 resulted in reactivation of autophagy in a subpopulation of HCT116 cells and increased proliferation. Accordingly, the senescent HCT116 cells treated with BAF A1 when injected into NOD/SCID mice formed tumors, in contrast to the controls.Our results suggest that senescent cancer cells that appear during therapy, can be considered as dormant cells that contribute to cancer re-growth, when chemotherapeutic treatment is stopped. These data unveil new mechanisms of TIS-related cancer maintenance and re-population, triggered by a single pulse of BAF A1 treatment.
authors.affiliation: Laboratory of Molecular Basis of Ageing, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland.|Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland.
authors.forename: Halina
authors.initials: H
authors.lastname: Was
authors.affiliation: Laboratory of Molecular Basis of Ageing, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland.|Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland.
authors.forename: Kamila
authors.initials: K
authors.lastname: Barszcz
authors.affiliation: Laboratory of Molecular Basis of Ageing, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland.|Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Czarnecka
authors.affiliation: Laboratory of Cytometry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Kowalczyk
authors.affiliation: Laboratory of Imaging Tissue Structure and Function, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland.
authors.forename: Tytus
authors.initials: T
authors.lastname: Bernas
authors.affiliation: Laboratory of Animal Models, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Uzarowska
authors.affiliation: Laboratory of Animal Models, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland.|Laboratory of Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Koza
authors.affiliation: Laboratory of Animal Models, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Klejman
authors.affiliation: Laboratory of Cytometry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Piwocka
authors.affiliation: Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland.
authors.forename: Bozena
authors.initials: B
authors.lastname: Kaminska
authors.affiliation: Laboratory of Molecular Basis of Ageing, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland.
authors.forename: Eva
authors.initials: E
authors.lastname: Sikora
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D016922:Cellular Senescence / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011003:Ploidies; D058985:Side-Population Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D047368:Tumor Burden
chemical_list: D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; D018942:Macrolides; D004317:Doxorubicin; C040929:bafilomycin A1
keywords: angiogenesis; autophagy; chemotherapy; colon cancer; senescence