Disturbed balance of expression between XIAP and Smac/DIABLO during tumour progression in renal cell carcinomas

Abstract

Dysregulation of apoptosis plays an important role in tumour progression and resistance to chemotherapy. The X-linked inhibitor of apoptosis (XIAP) is considered to be the most potent caspase inhibitor of all known inhibitor of apoptosis-family members. Only recently, an antagonist of XIAP has been identified, termed Smac/DIABLO. To explore the relevance of antiapoptotic XIAP and proapoptotic Smac/DIABLO for tumour progression in renal cell carcinomas (RCCs), we analysed XIAP and Smac/DIABLO mRNA and protein expression in the primary tumour tissue from 66 RCCs of all major histological types by quantitative real-time PCR, Western blot and ELISA. X-linked inhibitor of apoptosis and Smac/DIABLO mRNA expression was found in all RCCs. Importantly, the relative XIAP mRNA expression levels significantly increased from early (pT1) to advanced (pT3) tumour stages (P ¼ 0.0002) and also with tumour dedifferentiation (P ¼ 0.04). Western blot analysis confirmed the tumour stage-dependent increase of XIAP expression on the protein level. In contrast, mRNA and protein expression levels of Smac/DIABLO did not significantly change between early and advanced tumour stages or between low and high tumour grades. Consequently, the mRNA expression ratio between antiapoptotic XIAP and proapoptotic Smac/DIABLO markedly increased during progression from early (pT1) to advanced (pT3) tumour stages. Moreover, RCCs confined within the organ capsule (pT1 and pT2) exhibited a significantly lower XIAP to Smac/DIABLO expression ratio when compared with RCCs infiltrating beyond the kidney (pT3; P ¼ 0.01). Thus, our investigation demonstrates that the delicate balance between XIAP and Smac/DIABLO expression is gradually disturbed during progression of RCCs, resulting in a relative increase of antiapoptotic XIAP over proapoptotic Smac/DIABLO, thereby probably contributing to the marked apoptosis resistance of RCC.

Double inhibition of XIAP and Bcl-2 axis is beneficial for retrieving sensitivity of renal cell cancer to apoptosis

“…The present immunohistochemical data are consistent with previous reports that XIAP expression was increased in RCC compared with normal kidney and XIAP levels Yan et al, 2004;Mizutani et al, 2007) correlated with tumour progression. Despite several previous attempts, there is still no consensus on the significance of Smac to the malignant potential of RCC (Yan et al, 2004;Mizutani et al, 2005).…”

“…Despite several previous attempts, there is still no consensus on the significance of Smac to the malignant potential of RCC (Yan et al, 2004;Mizutani et al, 2005). Here, we found that Smac levels were lower in RCC than in normal kidney; however, the levels were similar in various tumour tissues.…”

“…Moreover, XIAP antisense oligonucleotide chemosensitised UC to adriamycin. It has also been shown that XIAP expression levels increased with the progression of RCC Yan et al, 2004;Mizutani et al, 2007). In addition, an XIAP antisense oligonucleotide sensitised RCC to Fas/TRAIL-induced apoptosis (Mizutani et al, 2007).…”

Validation of pharmacodynamic assays to evaluate the clinical efficacy of an antisense compound (AEG 35156) targeted to the X-linked inhibitor of apoptosis protein XIAP

“…Thus, it can antagonise both the mitochondrial regulated (intrinsic) and death-receptormediated (extrinsic) apoptotic pathways (Hengartner, 2000). In clinical investigations, the protein has been shown to be overexpressed in a number of different tumours relative to normal tissue (Hofmann et al, 2002;Krajewska et al, 2003;Shiraki et al, 2003) and high expression is often associated with poor patient outcome (Tamm et al, 2000(Tamm et al, , 2004Ramp et al, 2004;Yan et al, 2004) and resistance to chemotherapy (Parton et al, 2002).…”

Acquired chemoresistance in pancreatic carcinoma cells: induced secretion of IL-1β and NO lead to inactivation of caspases

“…In this context, the functional loss of the tumor-suppressor p53 (Brown and Attardi, 2005), the upregulation of antiapoptotic molecules, for example, bcl-2, c-FLIP, XIAP (Medema et al, 1999;Kim et al, 2004;Yan et al, 2004), or the downregulation of proapoptotic proteins, for example Smac/Diabolo and Bid (Erler et al, 2004;Yan et al, 2004), have been extensively reported. Another important determinant of antiapoptotic protection in cancer cells, including PDAC, is the constitutive activation of the transcription factor NF-kB (Wang et al, 1999;Schmid and Adler, 2000).…”