The topoisomerase II inhibitor teniposide (VM-26) induces apoptosis in unstimulated mature murine lymphocytes

Roy, Chitra; Brown, David L.; Little, Judy E.; Valentine, Beatrice K.; Walker, P. Roy; Sikorska, Marianna; Leblanc, Julie; Chaly, Nathalie

doi:10.1016/0014-4827(92)90190-j

Cited by 90 publications

(45 citation statements)

References 34 publications

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“…20 Further evidence for the involvement of ubiquitin genes in apoptosis came from studies of murine lymphocytes treated with teniposide. 21 However, the finding that HDACi activates UbB and favors apoptosis by elevating the UbB transcription and level of free cellular ubiquitin selectively in tumor cells has not been recognized earlier. Indeed, identification of UbB as the essential regulator in selective apoptosis of tumor cells is somehow unanticipated in that UbB was believed to be ubiquitously abundant in both normal and tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin B: an essential mediator of trichostatin A-induced tumor-selective killing in human cancer cells

Chen

Wang

et al. 2009

Cell Death Differ

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Although histone deacetylase inhibitors (HDACis) are emerging as a new class of anticancer agents, the mechanism of tumorselective killing by HDACi is not well understood. We used suppression of mortality by antisense rescue technique (SMART) to screen the key genes responsible for the tumor-selective killing by trichostatin A (TSA). Twenty-four genes were identified, the most significant of which was ubiquitin B (UbB). The expression of UbB was selectively upregulated by TSA in tumor cells, but not non-malignant cells. Further observation indicated that TSA induced a substantial dissipation of mitochondrial transmembrane potential, release of cytochrome c into the cytosol, and proteolytic cleavage of caspases-3/9 in HeLa cells, which was apparently mediated by ubiquitylation and the subsequent degradation of mitochondrial membrane proteins including BCL-2 and MCL-1. In contrast, knockdown of UbB expression inhibited the TSA-induced apoptotic cascade by abolishing TSA-induced ubiquitylation and the subsequent degradation of mitochondrial membrane proteins. Furthermore, apicidine, another HDACi, exhibited activity similar to that of TSA. Interestingly, TSA induced UbB-dependent proteasomal degradation of BCR-ABL fusion protein in K562 leukemic cells. Thus, our findings highlight the essential role of UbB and UbBdependent proteasomal protein degradation in HDACi-induced tumor selectivity. The mechanism provides a novel starting point for dissecting the molecular mechanism underlying the tumor selectivity of HDACi. 1-3 The clinical potential of HDACis has been well exemplified by the successful development of Vorinostat, which was recently approved by the US Food and Drug Administration for treatment of cutaneous T-cell lymphoma. 4 Despite the rapid clinical progress achieved, the mechanism of action of HDACis is not yet well understood. One of the central questions is how these agents selectively kill tumor cells while sparing normal cells. Identification of the critical intracellular targets responsible for the tumor selectivity of HDACis will further improve the design of optimized clinical protocols. More attractively, unraveling the potential 'death programs' selectively activated in tumor but not in normal cells will have broader implications for the understanding of tumorigenesis and the design of targeted therapies.Identification of the target genes essential for the selective induction of apoptosis in tumor cells has proven to be very difficult. It is well established that HDACis could affect up to 10% of all known genes at the transcriptional level. 5 In addition to HDACs, many non-histone proteins are also regulated by HDACis by influencing the molecular events of acetylation, protein-protein interactions and stability, and so on. Previously, a significant number of apoptotic and cell-cycle regulatory genes have been identified by different groups and proposed to be effectors responsible for the tumorselective action of HDACis. 6 In acute promyelocytic leukemia, however, preferential induction of tumor-n...

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Section: Discussionmentioning

confidence: 99%

Ubiquitin B: an essential mediator of trichostatin A-induced tumor-selective killing in human cancer cells

Chen

Wang

et al. 2009

Cell Death Differ

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“…While bleomycin and etoposide maximally kill cells in S-phase, where replication forks are forced to negotiate either cleaved complex / double strand breaks (etoposide; Bae et al., 1988) or double-strand breaks resulting from free-radical attack (bleomycin; Kuo, 1981), they can damage and kill cells in GO/GI (Roy et al, 1992;Clarke et al, 1993;Evans et al, 1994). In cell lines derived from clinically sensitive human tumours, DNA injury-induced wild-type p53 was held to be responsible for decreased clonogenicity following ionising radiation and this effect could be reversed by transfection of a dominant negative mutant p53.…”

Section: Resultsmentioning

confidence: 99%

p53-independent death and p53-induced protection against apoptosis in fibroblasts treated with chemotherapeutic drugs

Malcomson

Oren²,

Wyllie³

et al. 1995

Br J Cancer

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“…19 Further evidence for the involvement of ubiquitin in apoptosis came from studies of murine lymphocytes treated with teniposide, which induced a bright cytoplasmic ubiquitin staining pattern distinct from the nuclear immunofluorescence of control cells. 20 In the colonial ascidian Botryllus schlosseri, increased ubiquitin protein levels were noted in stomach, branchial basket, and intestinal tissues undergoing apoptosis. 21 Human lymphocytes exposed to g-irradiation revealed increased ubiquitin immunofluorescence in cells with apoptotic nuclear morphologies 1 ± 4 h after irradiation, even before visible chromatin changes.…”

Section: Correlation Of Apoptosis With Ubiquitinationmentioning

confidence: 99%

The role of the ubiquitin-proteasome pathway in apoptosis

1999

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Coordinated intracellular protein degradation mediated by the ubiquitin-proteasome pathway is crucial to a vast array of cellular processes including orderly progression through the mitotic cycle. Similarly important to both the fates of individual cells, as well as to the normal function of multicellular organisms, is the process of apoptosis, or programmed cell death. Execution of this latter process has been known for some time to be intimately associated with the activity of caspases, a family of proteases related to interleukin-1-b-converting enzyme. Evidence is now accumulating, however, that the ubiquitin-proteasome system itself plays an important role in apoptosis, and some of the cellular pathways that are impacted upon by the proteasome, and may lead to apoptosis, are beginning to be dissected. This review provides a summary of the experimental basis by which components of the ubiquitinproteasome pathway have been linked to apoptosis, and attempts are made to formulate a hypothesis about its role in this process.

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The topoisomerase II inhibitor teniposide (VM-26) induces apoptosis in unstimulated mature murine lymphocytes

Cited by 90 publications

References 34 publications

Ubiquitin B: an essential mediator of trichostatin A-induced tumor-selective killing in human cancer cells

Ubiquitin B: an essential mediator of trichostatin A-induced tumor-selective killing in human cancer cells

p53-independent death and p53-induced protection against apoptosis in fibroblasts treated with chemotherapeutic drugs

The role of the ubiquitin-proteasome pathway in apoptosis

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