Downregulation of Smac/DIABLO Expression in Renal Cell Carcinoma and Its Prognostic Significance

Mizutani, Yoichi; Nakanishi, Hiroyuki; Yamamoto, Kosuke; Li, Yong Nan; Matsubara, Hiroki; Mikami, Kōichi; Okihara, Koji; Kawauchi, Akihiro; Bonavida, Benjamin; Miki, Tsuneharu

doi:10.1200/jco.2005.02.191

Cited by 102 publications

(77 citation statements)

References 21 publications

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“…Smac/DIABLO accelerates XIAP autoubiquitination and self degradation and modulates protein expression levels. Noteworthy, we have recently reported in RCC that the expression of Smac/DIABLO is significantly decreased and is an independent prognostic factor for RCC (21). Thus, it is possible that the down-regulation of Smac/ DIABLO contributed, in large part, to the stabilization and high level of XIAP expression in RCC.…”

Section: Discussionmentioning

confidence: 99%

“…Smac/DIABLO binds to XIAP, displaces XIAP from caspase-9, promotes cleavage of effector caspases, and induces apoptosis (6,39). In addition, our previous study demonstrated that Smac/DIABLO expression was downregulated in RCC, and that no Smac/DIABLO expression in RCC predicted a worse prognosis (21). Therefore, the measurement of Smac/DIABLO expression as well as XIAP expression may be necessary for an accurate prediction of prognosis in RCC patients and an accurate evaluation of the efficacy of the therapy using XIAP antagonists in combination with immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…The presence of XIAP protein was determined in cell lysates by Western blot analysis as previously described (21). Briefly, 20 μg of the sample proteins was electrophoresed on 7.5% polyacrylamide gels in Tris-glycin buffer and transferred onto nitrocellulose membranes.…”

Section: Methodsmentioning

confidence: 99%

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Overexpression of XIAP expression in renal cell carcinoma predicts a worse prognosis

Mizutani¹,

Nakanishi²,

Li³

et al. 2007

Int J Oncol

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Abstract. X-linked inhibitor of apoptosis protein (XIAP) is the most potent caspase-inhibitory IAP family member and a negative regulator of various apoptotic stimuli. Thus, XIAP overexpression in cancer cells may select for tumor cell survival following various cytotoxic therapeutic modalities. The anatomical staging system in renal cell carcinoma (RCC) currently provides good prognostic information, albeit insufficient. We hypothesize that overexpression of XIAP in RCC may serve as a molecular prognostic marker in RCC and improve the staging of RCC. This study examined the protein level of XIAP in lysates from surgical specimens of 109 patients with RCC and 109 normal kidney specimens from the same patients. The level of XIAP expression was quantified by Western blot analysis using non-fixed fresh frozen tissues of RCCs and normal kidneys. Results indicated that the mean level of XIAP expression was higher in RCC compared to autologous normal kidney, and the XIAP expression level in 38/109 (35%) of RCC was more than 2-fold greater than that in normal kidney tissue. In Stage I/II RCC, the mean XIAP expression level was almost identical to that detected in normal kidney, whereas XIAP expression in Stage III/IV was 2.5-fold higher than that in Stage I/II RCC. Levels of XIAP expression also correlated with the grade of RCC. Patients with RCC with low XIAP expression had a longer postoperative disease-specific survival as compared to those with high expression in the 5-year follow-up. The suggested role of XIAP in the regulation of resistance in apoptosis was examined in vitro following treatment of RCC cell lines with XIAP antisense oligonucleotide and the cells were sensitized to both Fas-mediated and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. The present study demonstrates at the protein level that XIAP is overexpressed in RCC, and that high XIAP expression in RCC predicted a worse prognosis. In addition, XIAP antisense oligonucleotide sensitized RCC to Fas/TRAILinduced apoptosis. These results suggest that XIAP expression in RCC may be used as a prognostic parameter, and that downregulation or inhibition of XIAP expression in RCC may reverse immune resistance. IntroductionRenal cell carcinoma (RCC) accounts for approximately 2% of all cancer cases worldwide (1). Metastatic disease is often present at the time of diagnosis of RCC and its poor response to chemotherapy and radiotherapy determines its poor prognosis (2). Immunotherapy is relatively effective for RCC, however, the response rate is approximately 20% (3). Therefore, new therapeutic approaches are necessary for these patients with metastatic RCC.The aggressive stage of cancer is characterized by the appearance of apoptosis-resistant cells as a result of various genetic mutations and overexpression of anti-apoptotic factors. Apoptosis can be achieved by a number of ligand receptor families, commonly called death receptors and also by various drugs or stress-induced stimuli. Death receptors bind to their respectiv...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Overexpression of XIAP expression in renal cell carcinoma predicts a worse prognosis

Mizutani¹,

Nakanishi²,

Li³

et al. 2007

Int J Oncol

Self Cite

View full text Add to dashboard Cite

show abstract

“…In particular, downregulation of the mitochondrial IAP antagonist Smac/DIABLO is associated with renal cell carcinomas, and overexpression of survivin, another IAP, has been observed in most transformed cell lines and cancers tested to date, as compared with its absence in most normal adult tissues. 12,13 Although there is evidence suggesting an indirect caspase-9 processing interference by survivin, 14 malfunctions of mitotic spindle checkpoint and aberrant progression of transformed cells may be due to non-apoptotic functions of this particular IAP. 15 Association between X-linked inhibitor of apoptosis protein (XIAP) overexpression and poor clinical outcome has been reported for both renal cell carcinomas and acute myelogenous leukemia (AML).…”

Section: Apoptosis As a Defense Strategy Against Tumorogenesismentioning

confidence: 99%

Caspases and cancer

2011

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Evasion of apoptosis is considered to be one of the hallmarks of human cancers. This cell death modality is executed by caspases and several upstream regulatory factors, which direct their proteolytic activity, have been defined as either tumor suppressors or oncogenes. Often these regulatory factors, in addition to being potent apoptosis inducers, function in cell survival or repair signaling pathways in response to cellular stress. Thus, loss of function in a distinct regulatory mechanism does not necessarily mean that tumor formation is due to apoptosis malfunction resulting from insufficient caspase activation. Although each caspase has been assigned a distinct role in apoptosis, some redundancy with respect to their regulatory functions and substrate recognition is evident. Jointly, these proteases could be considered to possess solid tumor suppressor function, but what is the evidence that deregulation of specific caspases per se induces inappropriate cell survival, leading to enhanced tumorigenic potential? This question will be addressed in this review, which covers basic molecular mechanisms derived from in vitro analyses and emphasizes new insights that have emerged from in vivo and clinical studies. In organisms, excess cells during development, as well as potentially harmful cells resulting from pathophysiological conditions, are eliminated by various cell death modalities. Among them, apoptosis is the most investigated, and almost 40 years ago, it was described as a major defense strategy that prevents cells from acquiring tumorigenic potential. 1 This suicide mechanism is controlled by multiple and interrelated pathways ensuring that caspases, the proteolytic initiators and executioners of apoptosis, are triggered only in cells requiring termination. There is overwhelming experimental evidence supporting the idea that disturbances in the regulation of caspase activation are central for the avoidance of cancer cell death, both in vitro and in vivo. However, what evidences suggest that caspases per se act as tumor suppressors? It was reported that cells do not necessarily undergo caspaseindependent cell death in the absence of active caspases, but may instead survive insult and even promote clonogenic tumor growth. 2 Yet, it was unclear which individual caspases could fulfill this function. Recently, certain initiator caspases have been suggested as putative tumor suppressor genes. 3,4 This review is focusing on caspases and their role in tumor suppression, and emphasizing new evidences that have emerged from in vivo observations and clinical material, taking into consideration supporting in vitro data that has enlightened basic molecular mechanisms. CaspasesClassification of human caspases is based either on their function, the size of their pro-domain or cleavage specificity.Considering the first criteria, caspase-1, -4 and -5 belong to the group I (inflammatory) caspases that are involved in cytokine maturation. These proteases are primarily associated with the innate immunity against pathogens an...

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“…Note Smac protein expression is downregulated in RCC and no expression of Smac predicts a worse prognosis (Mizutani et al, 2005). Either Smac mRNA expression is inversely associated with outcome of RCC patients (Kempkensteffen et al, 2008a).…”

Section: Renal Cell Carcinomamentioning

confidence: 99%