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

• Published in: British journal of cancer Vol. 91; no. 7; pp. 1349 - 1357
• Main Authors: YAN, Y, MAHOTKA, C, RAMP, U, HEIKAUS, S, SHIBATA, T, WETHKAMP, N, LIEBMANN, J, SUSCHEK, C. V, GUO, Y, GABBERT, H. E, GERHARZ, C. D
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 04-10-2004
• Subjects: Apoptosis; Apoptosis - genetics; Apoptosis Regulatory Proteins; Biological and medical sciences; Blotting, Western; Cancer research; Cancer therapies; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; Carrier Proteins - biosynthesis; Disease Progression; Enzyme-Linked Immunosorbent Assay; Gene Expression Profiling; Humans; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Kidneys; Medical research; Medical sciences; Mitochondria; Mitochondrial Proteins - biosynthesis; Molecular and Cellular Pathology; Nephrology. Urinary tract diseases; Polymerase Chain Reaction; Protein Biosynthesis; Protein expression; Proteins; Tumors; Tumors of the urinary system; X-Linked Inhibitor of Apoptosis Protein; Zinc Fingers; Germany; Kidney disease; direct IAP-binding protein with low pl; Sex linked character; Urinary system disease; Carcinoma; tumour progression; Malignant tumor; X-linked inhibitor of apoptosis; Binding protein; renal cell carcinoma; Cancerology; Tumor progression; second mitochondria-derived activator of caspases; Grawitz tumor; Inhibitor; X-Chromosome; Second mitochondria derived activator of caspase; Balance; Tumor cell; Apoptosis
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6602127

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=0.0002) and also with tumour dedifferentiation (P=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=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.