Proteasomal inhibition potentiates drugs targeting DNA topoisomerase II

Lee, Ka C.; Bramley, Rebecca L.; Cowell, Ian G.; Jackson, Graham; Austin, Caroline A.

doi:10.1016/j.bcp.2015.12.015

Cited by 40 publications

(44 citation statements)

References 59 publications

(87 reference statements)

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“…This was confirmed in human cells lacking TOP2B , where TOP2B null cells showed the greatest resistance to mAMSA and mitoxantrone, and also showed resistance to etoposide and doxorubicin. Notably, in this study TOP2B −/− null cells were significantly less sensitive to mAMSA and mitoxantrone than were TOP2A +/− heterozygotes, while for etoposide the TOP2A, heterozygotes demonstrated the greatest resistance [ 68 , 69 ]. Further evidence for targeting of TOP2B by TOP2 poisons was provided using a yeast ts top2 system expressing functional human TOP2B.…”

Section: Top2b As An Anti-cancer Drug Targetmentioning

confidence: 91%

TOP2B: The First Thirty Years

Austin

Lee

Swan

et al. 2018

IJMS

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Type II DNA topoisomerases (EC 5.99.1.3) are enzymes that catalyse topological changes in DNA in an ATP dependent manner. Strand passage reactions involve passing one double stranded DNA duplex (transported helix) through a transient enzyme-bridged break in another (gated helix). This activity is required for a range of cellular processes including transcription. Vertebrates have two isoforms: topoisomerase IIα and β. Topoisomerase IIβ was first reported in 1987. Here we review the research on DNA topoisomerase IIβ over the 30 years since its discovery.

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Section: Top2b As An Anti-cancer Drug Targetmentioning

confidence: 91%

TOP2B: The First Thirty Years

Austin

Lee

Swan

et al. 2018

IJMS

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“…In this configuration, each protomer of the homodimeric TOP2 enzyme is covalently coupled to a cleaved DNA strand via a 5′-phosphotyrosine linkage. TOP2 poisons such as etoposide and mitoxantrone exert their tumoricidal effect by stabilizing this normally transient enzyme-bridged break, resulting in the accumulation of cytotoxic covalently linked TOP2 protein-DNA complexes, which can be processed in the cell to DNA double-strand breaks (Burma et al, 2001; Cowell and Austin, 2012; Lee et al, 2012, 2016). Therapy related leukemias, especially those appearing after exposure to TOP2 poisons often contain recurrent chromosome translocations, including t(15,17)(PML-RARA) , t(8,21)(AML-ETO) , and 11q23 rearrangements involving the MLL gene (Rowley and Olney, 2002; Cowell and Austin, 2012).…”

Section: Introductionmentioning

confidence: 99%

Myeloperoxidase Enhances Etoposide and Mitoxantrone-Mediated DNA Damage: A Target for Myeloprotection in Cancer Chemotherapy

et al. 2016

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Myeloperoxidase is expressed exclusively in granulocytes and immature myeloid cells and transforms the topoisomerase II (TOP2) poisons etoposide and mitoxantrone to chemical forms that have altered DNA damaging properties. TOP2 poisons are valuable and widely used anticancer drugs, but they are associated with the occurrence of secondary acute myeloid leukemias. These factors have led to the hypothesis that myeloperoxidase inhibition could protect hematopoietic cells from TOP2 poison-mediated genotoxic damage and, therefore, reduce the rate of therapy-related leukemia. We show here that myeloperoxidase activity leads to elevated accumulation of etoposide- and mitoxantrone-induced TOP2A and TOP2B-DNA covalent complexes in cells, which are converted to DNA double-strand breaks. For both drugs, the effect of myeloperoxidase activity was greater for TOP2B than for TOP2A. This is a significant finding because TOP2B has been linked to genetic damage associated with leukemic transformation, including etoposide-induced chromosomal breaks at the MLL and RUNX1 loci. Glutathione depletion, mimicking in vivo conditions experienced during chemotherapy treatment, elicited further MPO-dependent increase in TOP2A and especially TOP2B-DNA complexes and DNA double-strand break formation. Together these results support targeting myeloperoxidase activity to reduce genetic damage leading to therapy-related leukemia, a possibility that is enhanced by the recent development of novel specific myeloperoxidase inhibitors for use in inflammatory diseases involving neutrophil infiltration.

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“…Therefore, specifically blocking the degradation of TOP2β would be a better choice for effectively enhancing the anticancer efficacy of TOP2 poisons. However, the proteasomal inhibitors used in a previous study are associated with high normal cell toxicity, as a result of the global inhibition of protein degradation through the 26 S proteasome 35 . In this study, we revealed the precise mechanism by which TOP2 poisons induce TOP2β degradation and demonstrated that specifically blocking TOP2β degradation remarkably sensitizes cancer cells to VM-26 treatment (Fig.…”

Section: Discussionmentioning

confidence: 98%

“…A previous study showed that proteasomal inhibitors significantly enhance the growth inhibition of drugs targeting DNA topoisomerase II, indicating that blocking TOP2 degradation is an attractive strategy to sensitize cancer cells to TOP2-targeting chemotherapeutic drugs (TOP2 poisons) 35 . Although TOP2 poisons induce the degradation of both TOP2α and TOP2β, the rate and extent of degradation are much greater for TOP2β than for TOP2α ( Fig.…”

Section: Discussionmentioning

confidence: 99%

SCFβ-TrCP-mediated degradation of TOP2β promotes cancer cell survival in response to chemotherapeutic drugs targeting topoisomerase II

Shu

Cui

et al. 2020

Oncogenesis

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Topoisomerase II (TOP2)-targeting anticancer chemotherapeutic drugs, termed TOP2 poisons, are widely used and effective in the clinic by stabilizing TOP2-DNA covalent complexes to induce DNA double-strand breaks (DSBs) and ultimately, cause cell death. The stabilized TOP2-DNA complex is known to be degraded by proteasome, whereas the underlying mechanism for instant TOP2β degradation in response to TOP2 poisons and the subsequent biological consequence remain elusive. Here, we reported that TOP2 poison-induced TOP2β degradation is mediated by SCF β-TrCP ubiquitin ligase. Specifically, DNA damage signal, triggered by teniposide (VM-26) treatment, activates ATM, cooperating with CK1 to phosphorylate TOP2β on Ser1134 and Ser1130, respectively, in a canonical degron motif to facilitate β-TrCP binding and subsequent degradation. Inactivation of ATM, CK1 or SCF β-TrCP by small molecular inhibitors or genetic knockdown/knockout abrogates TOP2β degradation. Biologically, blockage of TOP2β degradation in combination with VM-26 treatment impairs DNA damage response and repair, leading to an accelerated cell death via apoptosis. Thus, it appears that TOP2β degradation is a cellular defensive mechanism to facilitate the exposure of DSBs to trigger DNA damage response and repair. Collectively, our findings reveal a new strategy to improve the efficacy of TOP2 poisons in combination with small-molecule inhibitors against TOP2β degradation.

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Proteasomal inhibition potentiates drugs targeting DNA topoisomerase II

Abstract: Graphical abstract

Cited by 40 publications

References 59 publications

TOP2B: The First Thirty Years

TOP2B: The First Thirty Years

Myeloperoxidase Enhances Etoposide and Mitoxantrone-Mediated DNA Damage: A Target for Myeloprotection in Cancer Chemotherapy

SCFβ-TrCP-mediated degradation of TOP2β promotes cancer cell survival in response to chemotherapeutic drugs targeting topoisomerase II

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