Induction of senescence with doxorubicin leads to increased genomic instability of HCT116 cells.
Induction of senescence has been proposed as a possible in vivo tumor response to anticancer treatment. Senescent cancer cells are often polyploid, however, their route to polyploidy is poorly recognized (endoreduplication versus aberrant mitoses). We showed that after treatment of HCT116 cells with a low dose of doxorubicin most of them stopped proliferation as documented by SA-beta-galactosidase activity and the lack of Ki67 expression. Increased expression of other common senescence markers, p53, p21 and cyclin D1, was also observed. The cells became giant, polyploid and polymorphic, with multinucleated cells comprising a substantial fraction. The vast majority of the doxorubicin-treated cells did not enter mitoses, as evidenced by mitotic index analysis, as well as by the predominantly cytoplasmic localization of cyclin B1 and a lack of separation of multiplied centrosomes. This allowed us to conclude that doxorubicin-treated HCT116 cells underwent endoreduplication. However, the rare events of aberrant mitoses of polyploid cells observed by us led to aneuploid progeny as was documented by cytogenetic analysis of survivors. Thus, a senescence-inducing treatment of HCT116 cancer cells had a dual effect-it stopped the proliferation of the majority of the cells, but also led to the appearance of proliferating aneuploid ones.
Department of Biochemistry, Nencki Institute of Experimental Biology, Pasteura 3, 02-093 Warsaw, Poland.
Malgorzata A
MA
Sliwinska
Grazyna
G
Mosieniak
Kamila
K
Wolanin
Aneta
A
Babik
Katarzyna
K
Piwocka
Adriana
A
Magalska
Joanna
J
Szczepanowska
Jan
J
Fronk
Ewa
E
Sikora
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D004261:DNA Replication / Q000187:drug effects; D018450:Disease Progression; D004317:Doxorubicin / Q000494:pharmacology*; D042822:Genomic Instability / Q000187:drug effects*; D045325:HCT116 Cells; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D011123:Polyploidy
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin