XIAP targeting sensitizes Hodgkin lymphoma cells for cytolytic T-cell attack

Kashkar, Hamid; Seeger, Jens M.; Hombach, Andreas; Deggerich, Anke; Yazdanpanah, Benjamin; Utermöhlen, Olaf; Heimlich, Gerd; Abken, Hinrich; Krönke, Martin

doi:10.1182/blood-2006-05-021675

Cited by 64 publications

(59 citation statements)

References 39 publications

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“…Resistance to apoptosis accompanied by uncontrollable cell division could promote growth of tumor mass in the nude mice. This working model is also supported by the knowledge that a G 2 /M checkpoint defect promotes tumorigenesis (3) and that there is close association of up-regulation of three such antiapoptotic proteins, Bcl-xL, XIAP, and cIAP2, with constitutive activation of NF-B and resistance to apoptosis in a variety of human malignancies (45)(46)(47)(48)(49)(50).…”

Section: Discussionmentioning

confidence: 73%

Tumor-suppressing Function of Caspase-2 Requires Catalytic Site Cys-320 and Site Ser-139 in Mice

Ren

Porollo

et al. 2012

Journal of Biological Chemistry

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Background: Caspase-2 deficiency accelerates tumorigenesis in mice, but the underlying mechanisms remain unclear. Results: Caspase-2 catalytic site Cys-320 and Ser-139 residues sustain G 2 /M checkpoint and inhibit transformation and NF-B activation. Conclusion: Both residues are required for caspase-2 to suppress tumorigenesis in nude mice. Significance: These findings provide insight into tumor suppression at the cross-roads of apoptosis, cell cycle checkpoint, and NF-B pathways.

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Section: Discussionmentioning

confidence: 73%

Tumor-suppressing Function of Caspase-2 Requires Catalytic Site Cys-320 and Site Ser-139 in Mice

Ren

Porollo

et al. 2012

Journal of Biological Chemistry

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“…87 CLL cells express high levels of XIAP, 88,89 rendering them relatively resistant to death receptor-mediated 90 or granzyme-mediated apoptosis. 91 We observed that inhibitors of XIAP could work synergistically with death receptor ligation to kill CD40-activated CLL cells in vitro. 92 Conceivably, such XIAP inhibitors could enhance the effectiveness of CD154-immune gene therapy.…”

Section: Improving the Capacity Of Cll To Function As Effective Antigmentioning

confidence: 94%

Cellular immune therapy for chronic lymphocytic leukemia

Kater

Oers

Kipps

2007

Blood

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Although chemotherapy can induce complete responses in patients with chronic lymphocytic leukemia (CLL), it is not considered curative. Treated patients generally develop recurrent disease requiring additional therapy, which can cause worsening immune dysfunction, myelosuppression, and selection for chemotherapyresistant leukemia-cell subclones. Cellular immune therapy promises to mitigate these complications and potentially provide for curative treatment. Most experience with this is in the use of allogeneic hematopoietic stem-cell transplantation (allo-HSCT), in which graft-versus-leukemia (GVL) effects can be observed and shown responsible for long-term disease-free survival. However, use of allo-HSCT for CLL is limited because of the lack of suitable donors and the treatment-related morbidity/mortality for elderly patients, who constitute the majority at risk for developing this disease. The GVL effect, however, suggests there are specific CLL-associated antigens that could be targeted in autologous cellular immune therapy. Effective strategies for this will have to overcome the disease-related acquired immune deficiency and the capacity of the leukemia-cell to induce T-cell tolerance, thereby compromising the activity of even conventional vaccines in patients with this disease. We will discuss the different strategies being developed to overcome these limitations that might provide for effective cellular immune therapy of CLL. IntroductionChronic lymphocytic leukemia (CLL) is a CD5 ϩ B-cell malignancy that is considered incurable. Historically, the first-line treatment consisted of alkylating agents, which resulted in response rates in up to 70% of patients, but did not improve survival. 1 Treatment regimens with the nucleoside (purine) analogs, such as fludarabine monophosphate (F-ara-A) or pentostatin, were found to yield higher response rates and to provide for longer progression-free survival, 2 especially in combination with cyclophosphamide. 3 However, despite effecting increased complete response rates, treatment with purine analogs alone does not appear to improve survival. 2 Newer treatment combinations have incorporated use of monoclonal antibodies to chemotherapy. 4,5 Although treatment with such combinations might provide for a first-time-observed survival benefit, 6 such therapy still is not considered curative.Although most patients initially respond to these chemotherapeutic approaches, many develop therapy-resistant disease with repeated therapy. Patients with refractory disease more frequently have leukemia cells that harbor deletions in the short arm of chromosome 17 (17pϪ), which often is associated with loss of functional p53, or in the long arm of chromosome 11 (11qϪ) in and/or around the gene encoding the ataxia telangectasia (ATM), which is a kinase required for p53 function. 7,8 Moreover, many chemotherapy-refractory patients have leukemia cells that have lost functional p53. Because the cytoreductive activity of most chemotherapy agents requires functional p53, 9,10 loss of p53 is ...

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“…If, indeed, the mitochondrial release of SMAC was responsible for the neutralisation of XIAP, then downregulation of SMAC should restore the caspase-inhibitory function of XIAP and increase resistance towards cytostatic agents. To address this issue, we stably downregulated SMAC expression using small hairpin RNA (shRNA) targeting SMAC mRNA (Kashkar et al, 2006) ( Figure 3A). As expected, HeLa-SMACshRNA cells showed a markedly reduced susceptibility to chemotherapeutic treatments compared with their parental counterparts, HeLa and HeLamycXIAP, and this was even more pronounced in the presence of XIAP overexpression shown in HeLa-mycXIAP-SMACshRNA cells ( Figure 3B and Supplementary Figure S2).…”

Section: Elevated Xiap Expression Does Not Confer Chemoresistancementioning

confidence: 99%

“…Stable cell lines were generated by blasticidin selection (Invitrogen) as described (Kashkar et al, 2006).…”

Section: Sirna and Lentiviral Gene Transfermentioning

confidence: 99%

Elevated XIAP expression alone does not confer chemoresistance

et al. 2010

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BACKGROUND: In various tumour types, elevated expression of the X-linked inhibitor of apoptosis protein (XIAP) has been observed and XIAP targeting in diverse tumour entities enhanced the susceptibility to chemotherapeutic agents. Therefore, XIAP has been described and reviewed repeatedly as a chemoresistance factor in different tumour entities. However, rather than being an adverse prognostic marker, recent data suggest that elevated XIAP expression may be associated with a favourable clinical outcome. These somewhat conflicting findings, and the fact that in early studies XIAP suppressed apoptosis only when expressed transiently at levels far in excess of its physiological concentration, argue that the function of XIAP as an anti-apoptotic factor in tumour cells is both more complex and diverse than previously appreciated. METHODS: To better understand the impact of long-term elevated XIAP expression on resistance to chemotherapy, we generated cell lines stably overexpressing XIAP. The role of mitochondria was examined by stable expression of Bcl2 or stable knockdown of second mitochondria-derived activator of caspase (SMAC) in combination with up-or downregulation of XIAP expression. RESULTS: Our data show that long-term expression of XIAP at concentrations comparable to that in tumour cells (two-to five-fold increase) resulted in little or no resistance towards chemotherapeutic drugs. The XIAP overexpression only in conjunction with stable knockdown of a single XIAP-antagonising factor such as SMAC resulted in severe resistance to cytostatic agents demonstrating XIAP as a potent chemoresistance factor only in cells lacking functional XIAP regulatory circuits. CONCLUSION: Our results demonstrated that elevated XIAP expression alone cannot serve as a predictive marker of chemoresistance. Our data suggest that in order to predict the impact of XIAP on chemosusceptibility for a given tumour entity, the expression levels and functional states of all XIAP modulators need to be taken into account.

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XIAP targeting sensitizes Hodgkin lymphoma cells for cytolytic T-cell attack

Cited by 64 publications

References 39 publications

Tumor-suppressing Function of Caspase-2 Requires Catalytic Site Cys-320 and Site Ser-139 in Mice

Tumor-suppressing Function of Caspase-2 Requires Catalytic Site Cys-320 and Site Ser-139 in Mice

Cellular immune therapy for chronic lymphocytic leukemia

Elevated XIAP expression alone does not confer chemoresistance

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