Bortezomib Sensitizes Pancreatic Cancer Cells to Endoplasmic Reticulum Stress-Mediated Apoptosis

Nawrocki, Steffan T.; Carew, Jennifer S.; Pino, Maria Simona; Highshaw, Ralph A.; Dunner, Kenneth; Huang, Peng; Abbruzzese, James L.; McConkey, David J.

doi:10.1158/0008-5472.can-05-2370

Cited by 289 publications

(269 citation statements)

References 41 publications

(49 reference statements)

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“…Furthermore, the dose-response of caspase-cleavage activity in cytoplasts was very similar to that of intact cells and apoptotic signaling in enucleated cells is inhibited by ROS scavengers. The previously reported cisplatin-induced increases in Ca 21 (i) and ER stress 9,15 are likely to be secondary to the formation of ROS.…”

Section: Cisplatin Induces Increases In Ca 21mentioning

confidence: 84%

“…9 At least part of this DNA-damage independent response may involve ER stress, since BiP/GRP78 expression and cleavage of ER stress-activated caspases are induced. 9,15 The ER stress response is generally characterized by a time-dependent refolding response, which is followed by a refolding and degradation response. 16 The latter response is mediated by the XBP1 transcription factor, and we investigated whether cisplatin induces splicing of the mRNA for this transcription factor, an event carried out by the IRE1 Rnase.…”

Section: Resultsmentioning

confidence: 99%

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Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA

Berndtsson

Hägg

Panaretakis

et al. 2006

Intl Journal of Cancer

196

162

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Cisplatin is a broad-spectrum anticancer drug that is also widely used in experimental studies on DNA damage-induced apoptosis. Induction of apoptosis within 24-48 hr requires cisplatin concentrations that are at least one order of magnitude higher than the IC 50 . Here, we show that such high, apoptosis-inducing cisplatin concentrations induce cellular superoxide formation and that apoptosis is inhibited by superoxide scavengers. The same concentration limit and the requirement for superoxide are also true for induction of caspase activation in enucleated cells (cytoplasts), showing that cisplatin-induced apoptosis occurs independently of nuclear DNA damage. In contrast, lower cisplatin concentrations, which do not induce acute apoptosis, are sufficient for induction of DNA damage signaling. We propose that the antiproliferative effects of cisplatin at IC 50 doses involve premature senescence and secondary, nonstress-induced apoptosis. The higher doses currently used in in vitro studies lead to acute, stress-induced apoptosis that involves induction of superoxide but is largely DNA damage-independent. ' 2006 Wiley-Liss, Inc.Key words: cisplatin; DNA damage; apoptosis; senescence Cis-diamminedichloroplatinum (II) (cisplatin) is a commonly used anticancer agent, especially effective in the treatment of testicular carcinoma and also used to treat other malignancies such as ovarian, cervix, head-and-neck and small-cell lung cancer. 1 Cisplatin forms covalent bonds to the N7 positions of DNA purines to form intra-or interstrand crosslinks, and DNA is generally acknowledged as the primary target of cisplatin. 2,3 Cisplatin is a commonly used model agent for induction of DNA damage-dependent apoptosis in vitro. Acute apoptosis is induced within 24-36 hr, and major efforts have been performed to elucidate apoptotic signaling pathways induced by cisplatin within this time frame. These various studies have highlighted the roles of c-ABL, stressactivated protein kinases and p53 as downstream mediators of cisplatin-induced DNA damage and as mediators of apoptotic signaling (recently reviewed in 3 ). In addition to induction of apoptosis, cisplatin also induces premature senescence. 4 Premature senescence is currently thought to be related to replicative senescence, which has been demonstrated to be a DNA damage response. 5 During replicative senescence, signaling pathways involving ATM (Ataxia telangiectasia mutated) and p53 are activated by telomere uncapping. 5,6 The same signaling mechanisms are believed to be involved in premature senescence induced by DNA damaging drugs. 6,7 Apoptosis and senescence are obviously mutually exclusive cellular outcomes. The factors that decide whether cisplatin will trigger apoptosis or senescence are not clearly understood. In one scenario, senescence and apoptosis represent graded responses to increasing DNA damage. In more complex scenarios, cisplatin induces senescence and apoptosis by different (or partially different) mechanisms.As inducer of apoptosis, cisplatin is used at very d...

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Section: Cisplatin Induces Increases In Ca 21mentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA

Berndtsson

Hägg

Panaretakis

et al. 2006

Intl Journal of Cancer

196

162

View full text Add to dashboard Cite

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“…A greater understanding of the regulation of the unfolded protein response has already proved critical in designing enhanced therapies for the prevention of tumor development and for generating new chemotherapeutics (69)(70)(71). Indeed, multiple approaches have investigated the XBP1 branch and its targets as a means to control human diseases (7,64,72,73).…”

Section: Discussionmentioning

confidence: 99%

MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response

Hess

Strelau

Karki

et al. 2016

Molecular and Cellular Biology

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Transcriptional networks that govern secretory cell specialization, including instructing cells to develop a unique cytoarchitecture, amass extensive protein synthesis machinery, and be embodied to respond to endoplasmic reticulum (ER) stress, remain largely uncharacterized. In this study, we discovered that the secretory cell transcription factor MIST1 (Bhlha15), previously shown to be essential for cytoskeletal organization and secretory activity, also functions as a potent ER stress-inducible transcriptional regulator. Genome-wide DNA binding studies, coupled with genetic mouse models, revealed MIST1 gene targets that function along the entire breadth of the protein synthesis, processing, transport, and exocytosis networks. Additionally, key MIST1 targets are essential for alleviating ER stress in these highly specialized cells. Indeed, MIST1 functions as a coregulator of the unfolded protein response (UPR) master transcription factor XBP1 for a portion of target genes that contain adjacent MIST1 and XBP1 binding sites. Interestingly, Mist1 gene expression is induced during ER stress by XBP1, but as ER stress subsides, MIST1 serves as a feedback inhibitor, directly binding the Xbp1 promoter and repressing Xbp1 transcript production. Together, our findings provide a new paradigm for XBP1-dependent UPR regulation and position MIST1 as a potential biotherapeutic for numerous human diseases.

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“…Since activation of c-Jun amino-terminal kinase (JNK) accompanies apoptosis induced by bortezomib, 41 we investigated the status of JNK phosphorylation. Measuring the increase of the fraction of phosphorylated species out of total JNK, we observed that both 7.5 nM bortezomib and TNF increased phosphorylation 5-to 6-fold, while the combination of both drugs increased phosphorylation almost 14-fold.…”

Section: Tnf Enhances Apoptosis Induced By Bortezomib In C-26 Cellsmentioning

confidence: 99%

TNF potentiates anticancer activity of bortezomib (Velcade®) through reduced expression of proteasome subunits and dysregulation of unfolded protein response

Nowis

McConnell

Dierlam

et al. 2007

Intl Journal of Cancer

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Bortezomib (Velcade 1 ) exploits proteasome inhibition as a unique mechanism of anticancer activity. The effectiveness of bortezomib is, however, limited, therefore, the search for therapeutic regimens combining bortezomib with other agents. In the present work we demonstrate enhanced anticancer activity of bortezomib by its combination with tumor necrosis factor (TNF) in the experimental model of C-26 colon carcinoma in mice. This interaction likely relies on the induction of a dysregulated response to ER stress, leading to apoptosis of cancer cells, evidenced by caspase-3 cleavage, p53 accumulation as well as increased SAPK/JNK phosphorylation. ER stress induced by the combination of TNF and bortezomib is corroborated by upregulation of BiP, PDI and calnexin as well as cleavage of caspase-12; however, in contrast to the classic pathway, it is also associated with decreased phosphorylation of eIF2a and prevention of XBP-1 splicing. TNF prevented the upregulation of Hsp27 induced by bortezomib, which may contribute to enhanced ER stress. Moreover, TNF interfered with bortezomib-induced upregulation of distinct subunits of the 26S proteasome. Bortezomib concentration used in this study was not sufficient to prevent TNF from inducing nuclear translocation of p65/RelA; however, the combination of both agents reduced total p65/RelA levels. Combined treatment of tumor-bearing mice with bortezomib and TNF not only inhibited tumor growth but also significantly prolonged animal survival. Therefore, combination of bortezomib with TNF is an attractive option for further clinical studies. ' 2007 Wiley-Liss, Inc.

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Bortezomib Sensitizes Pancreatic Cancer Cells to Endoplasmic Reticulum Stress-Mediated Apoptosis

Cited by 289 publications

References 41 publications

Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA

Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA

MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response

TNF potentiates anticancer activity of bortezomib (Velcade®) through reduced expression of proteasome subunits and dysregulation of unfolded protein response

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