title: Apoptosis resistance, mitotic catastrophe, and loss of ploidy control in Burkitt lymphoma.
abstract: Resistance to cell death is the major cause of chemotherapy failure in most kinds of cancers, including Burkitt lymphoma (BL). When analyzing therapy resistance in Burkitt lymphoma (BL), we discovered a link between apoptosis resistance and ploidy control. We therefore studied systematically a panel of 15 BL lines for apoptosis induction upon treatment with microtubule inhibitors and compared three types of microtubule toxins, i.e., paclitaxel, nocodazole and vincristine. We found an inverse relationship between apoptosis sensitivity and ploidy control. Thus, cells resistant to paclitaxel- or nocodazole-induced apoptosis underwent mitotic catastrophe and developed polyploidy (>4N). Mechanistically, apoptosis resistance was linked to failure of caspase activation, which was most pronounced in cells lacking the pro-apoptotic multidomain Bcl-2 homologs Bax and Bak. Pharmacological caspase inhibition promoted polyploidy upon exposure to paclitaxel and nocodazole supporting the relationship between resistance to apoptosis and polyploidization. Of note, vincristine induced persistent mitotic arrest but no loss of ploidy control. Considering targets to facilitate Bax/Bak-independent cell death and to avoid drug-induced mitotic catastrophe and consecutive mitotic catastrophe should be of great importance to overcome therapy resistance and therapy-related events that result in ploidy changes and tumor progression.
  
  
  CONCLUSIONS
  Inverse relation of apoptosis and polyploidy induction by paclitaxel or nocodazole in BL. Resistant cells undergo mitotic catastrophe and develop polyploidy. Lack of Bax/Bak confers resistance and leads to induction of polyploidy in BL. Intact apoptosis response protects from polyploidy as a result of mitotic catastrophe.
authors.affiliation: Clinical and Molecular Oncology, University Medical Center Charité and Max-Delbrück-Center for Molecular Medicine, Lindenberger Weg 80, 13125, Berlin-Buch, Germany.
authors.forename: Cindrilla
authors.initials: C
authors.lastname: Chumduri
authors.forename: Bernhard
authors.initials: B
authors.lastname: Gillissen
authors.forename: Anja
authors.initials: A
authors.lastname: Richter
authors.forename: Antje
authors.initials: A
authors.lastname: Richter
authors.forename: Ana
authors.initials: A
authors.lastname: Milojkovic
authors.forename: Tim
authors.initials: T
authors.lastname: Overkamp
authors.forename: Anja
authors.initials: A
authors.lastname: Müller
authors.forename: Christiane
authors.initials: C
authors.lastname: Pott
authors.forename: Peter T
authors.initials: PT
authors.lastname: Daniel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000473:pathology*; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D053938:DNA Fragmentation; D005434:Flow Cytometry; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000187:drug effects / Q000235:genetics*; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D011003:Ploidies; D011123:Polyploidy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
chemical_list: D061945:Caspase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D050257:Tubulin Modulators; D014750:Vincristine; D020169:Caspases; D017239:Paclitaxel; D015739:Nocodazole