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Prognostic significance of Smac/DIABLO expression in renal cell carcinoma

2005; Lippincott Williams & Wilkins; Volume: 23; Issue: 16_suppl Linguagem: Inglês

10.1200/jco.2005.23.16_suppl.4657

1527-7755

Yoichi Mizutani, Hiroyuki Nakanishi, Ken Yamamoto, T. Nakamura, Takuya Nomoto, Kazuya Mikami, K. Okihara, Kazuhito Yoneda, Akihiro Kawauchi, Takahiro Miki,

Cancer, Lipids, and Metabolism

4657 Background: Smac/DIABLO was recently identified as a protein that is released from mitochondria in response to apoptotic stimulus and promotes apoptosis by antagonizing inhibitor of apoptosis proteins. In addition, Smac/DIABLO plays an important regulatory role in the sensitization of cancer cells to drug-induced apoptosis. However, little is known about the significance of Smac/DIABLO in various cancers including renal cell carcinoma (RCC). This study examined Smac/DIABLO expression in 78 normal kidneys and 78 RCCs, and investigated the prognostic significance. Methods: The level of Smac/DIABLO expression was quantified by Western blotting using non-fixed fresh frozen tissues. Results: Smac/DIABLO expression was lower in RCC, compared to the autologous normal kidney. 64/78 (82%) of RCC expressed Smac/DIABLO and 18% were negative, whereas 100% of normal kidney 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 cisplatin-mediated and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in RCC. Conclusions: The current 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 cisplatin-induced and TRAIL-induced apoptosis. These findings 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. No significant financial relationships to disclose.