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Apoptosis resistance, mitotic catastrophe, and loss of ploidy control in Burkitt lymphoma

Item Type:Article
Title:Apoptosis resistance, mitotic catastrophe, and loss of ploidy control in Burkitt lymphoma
Creators Name:Chumduri, C. and Gillissen, B. and Richter, A. and Richter, A. and Milojkovic, A. and Overkamp, T. and Mueller, A. and Pott, C. and Daniel, P.T.
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.
Keywords:Mitotic Catastrophe, Aneuploidy, Apoptosis, Bax, Bak, Caspase, Animals, Mice
Source:Journal of Molecular Medicine
Page Range:559-572
Date:May 2015
Official Publication:https://doi.org/10.1007/s00109-014-1242-2
PubMed:View item in PubMed

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