Originally published as JCO Early Release 10.1200/JCO.2005.02.191 on November 30 2004

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

From the Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Microbiology, Immunology, and Molecular Genetics, Jonsson Comprehensive Cancer Center, UCLA School of Medicine, University of California at Los Angeles, Los Angeles, CA

Address reprint requests to Yoichi Mizutani, MD, Department of Urology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan; e-mail: ymizutan{at}koto.kpu-m.ac.jp

PURPOSE: Second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI (Smac/DIABLO) was recently identified as a protein that is released from mitochondria in response to apoptotic stimuli and promotes apoptosis by antagonizing inhibitor of apoptosis proteins. Furthermore, Smac/DIABLO plays an important regulatory role in the sensitization of cancer cells to both immune- and drug-induced apoptosis. However, little is known about the clinical significance of Smac/DIABLO in various cancers, including renal cell carcinoma (RCC). This study examined Smac/DIABLO expression in 78 healthy kidneys and 78 RCCs.

MATERIALS AND METHODS: The level of Smac/DIABLO expression was quantified by Western blot analysis using nonfixed fresh frozen tissues.

RESULTS: The expression of Smac/DIABLO was lower in RCC compared with the autologous normal kidney. Sixty-four (82%) of 78 of RCC expressed Smac/DIABLO, and 18% were negative, whereas 100% of normal kidney tissues were positive. In stage I/II RCC, 96% expressed Smac/DIABLO, whereas only 50% expressed Smac/DIABLO in stage III/IV. Smac/DIABLO expression inversely correlated with the grade of RCC. Patients with RCC expressing Smac/DIABLO had a longer postoperative disease-specific survival than those without Smac/DIABLO expression in the 5-year follow-up. Transfection with Smac/DIABLO cDNA enhanced tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) –mediated and cisplatin-mediated cytotoxicity in RCC.

CONCLUSION: The present study demonstrates for the first time that Smac/DIABLO expression was downregulated in RCC and that no Smac/DIABLO expression in RCC predicted a worse prognosis. In addition, transfection with Smac/DIABLO sensitized RCC to TRAIL/cisplatin-induced apoptosis. These results suggest that Smac/DIABLO expression in RCC may be used as a prognostic parameter, and that enhancement of Smac/DIABLO expression in RCC may potentiate immunotherapy and chemotherapy.

Supported in part by grants in aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology (No. 15390496), and from the US Department of Defense (DAMD17-02-1-0023; B.B.).

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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