Top

Journal of Cancer Research and Clinical Oncology

Published in:

01-05-2008 | Original Paper

Expression levels of the mitochondrial IAP antagonists Smac/DIABLO and Omi/HtrA2 in clear-cell renal cell carcinomas and their prognostic value

Authors: Carsten Kempkensteffen, Stefan Hinz, Frank Christoph, Hans Krause, Ahmed Magheli, Mark Schrader, Martin Schostak, Kurt Miller, Steffen Weikert

Published in: Journal of Cancer Research and Clinical Oncology | Issue 5/2008

Abstract

Purpose

Numerous molecular parameters are thought to be implicated in renal cell carcinoma (RCC) tumor biology and may therefore reflect the malignant potential of individual tumors. Their investigation may thus help to improve the postoperative management of RCC patients. This study characterized the mRNA expression levels and evaluated the prognostic effect of the mitochondrial inhibitor of apoptosis antagonists Smac/DIABLO and Omi/HtrA2 in tumor tissue from clear-cell RCC patients.

Methods

The relative gene expression (RGE) was analyzed by real-time RT-PCR in tumor tissue obtained from 85 patients (median follow-up: 47 months) following surgical treatment. Expression data was correlated to clinico-pathological variables and outcome.

Results

The RGE of Smac/DIABLO was lowest in patients with primary metastases, intermediate in those who progressed to metastatic disease, and highest in those who did not develop metastases during follow-up (P = 0.006). Expression levels of Smac/DIABLO and Omi/HtrA2 were strongly correlated with each other (Pearson coefficient 0.90). Recurrence-free and tumor-specific survival was shorter in patients with low Smac/DIABLO levels (P = 0.019 and P = 0.001) as well as in those with low Omi/HtrA2 tumor expression (P = 0.033 and P = 0.032). Contrary to Omi/HtrA2, low Smac/DIABLO levels were still predictive of a reduced time to recurrence (hazard rate 5.31; 95% CI: 1.16–24.21) and tumor-specific survival (hazard rate 4.24; 95% CI: 1.22–14.77) in explorative multivariate analysis.

Conclusions

The mRNA expression levels of the mitochondrial IAP antagonists Smac/DIABLO and Omi/HtrA2 are strongly inter-correlated, but do not relate to tumor stage or grade of RCC. Our data suggest that expression of Smac/DIABLO, but not Omi/HtrA2, is inversely associated with outcome of RCC patients.

Atzpodien J, Kirchner H, Hanninen EL, Deckert M, Fenner M, Poliwoda H (1993) Interleukin-2 in combination with interferon-alpha and 5-fluorouracil for metastatic renal cell cancer. Eur J Cancer 29A(Suppl 5):S6–S8PubMedCrossRef

Bleumer I, de Mulder PH, Mulders PF (2006) The role of adjuvant therapy in non-metastatic RCC. Can J Urol 13 (Suppl 2):57–62PubMedCrossRef

Cohen HT, McGovern FJ (2005) Renal-cell carcinoma. N Engl J Med 353:2477–2490PubMedCrossRef

Deveraux QL, Reed JC (1999) IAP family proteins: suppressors of apoptosis. Genes Dev 13:239–252PubMedCrossRef

Deveraux QL, Stennicke HR, Salvesen GS, Reed JC (1999) Endogenous inhibitors of caspases. J Clin Immunol 19:388–398PubMedCrossRef

Du C, Fang M, Li Y, Li L, Wang X (2000) Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102:33–42PubMedCrossRef

Fong WG, Liston P, Rajcan-Separovic E, St Jean M, Craig C, Korneluk RG (2000) Expression and genetic analysis of XIAP-associated factor 1 (XAF1) in cancer cell lines. Genomics 70:113–122PubMedCrossRef

Han KR, Bleumer I, Pantuck AJ, Kim HL, Dorey FJ, Janzen NK, Zisman A, Dinney CP, Wood CG, Swanson DA, Said JW, Figlin RA, Mulders PF, Belldegrun AS (2003) Validation of an integrated staging system toward improved prognostication of patients with localized renal cell carcinoma in an international population. J Urol 170:2221–2224PubMedCrossRef

Hegde R, Srinivasula SM, Zhang Z, Wassell R, Mukattash R, Cilenti L, DuBois G, Lazebnik Y, Zervos AS, Fernandes-Alnemri T, Alnemri ES (2002) Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J Biol Chem 277:432–438PubMedCrossRef

Holley CL, Olson MR, Colon-Ramos DA, Kornbluth S (2002) Reaper eliminates IAP proteins through stimulated IAP degradation and generalized translational inhibition. Nat Cell Biol 4:439–444PubMedCrossRef

Igney FH, Krammer PH (2002) Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer 2:277–288PubMedCrossRef

Janzen NK, Kim HL, Figlin RA, Belldegrun AS (2003) Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am 30:843–852PubMedCrossRef

Kaouk JH, Aron M, Rewcastle JC, Gill IS (2006) Cryotherapy: clinical end points and their experimental foundations. Urology 68:38–44PubMedCrossRef

Karge WH 3rd, Schaefer EJ, Ordovas JM (1998) Quantification of mRNA by polymerase chain reaction (PCR) using an internal standard and a nonradioactive detection method. Methods Mol Biol 110:43–61PubMed

LaCasse EC, Baird S, Korneluk RG, MacKenzie AE (1998) The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene 17:3247–3259PubMedCrossRef

Lam JS, Belldegrun AS, Figlin RA (2006) Adjuvant treatment for renal cell carcinoma. Expert Opin Pharmacother 7:705–720PubMedCrossRef

Levy DA, Slaton JW, Swanson DA, Dinney CP (1998) Stage specific guidelines for surveillance after radical nephrectomy for local renal cell carcinoma. J Urol 159:1163–1167PubMedCrossRef

Liston P, Fong WG, Kelly NL, Toji S, Miyazaki T, Conte D, Tamai K, Craig CG, McBurney MW, Korneluk RG (2001) Identification of XAF1 as an antagonist of XIAP anti-caspase activity. Nat Cell Biol 3:128–133PubMedCrossRef

Ljungberg B, Alamdari FI, Rasmuson T, Roos G (1999) Follow-up guidelines for nonmetastatic renal cell carcinoma based on the occurrence of metastases after radical nephrectomy. BJU Int 84:405–411PubMedCrossRef

Ma L, Huang Y, Song Z, Feng S, Tian X, Du W, Qiu X, Heese K, Wu M (2006) Livin promotes Smac/DIABLO degradation by ubiquitin-proteasome pathway. Cell Death Differ 13(12):2079–2088PubMedCrossRef

McLaughlin JK, Lipworth L (2000) Epidemiologic aspects of renal cell cancer. Semin Oncol 27:115–123PubMed

Mizutani Y, Nakanishi H, Yamamoto K, Li YN, Matsubara H, Mikami K, Okihara K, Kawauchi A, Bonavida B, Miki T (2005) Downregulation of Smac/DIABLO expression in renal cell carcinoma and its prognostic significance. J Clin Oncol 23:448–454PubMedCrossRef

Motzer RJ, Bander NH, Nanus DM (1996) Renal-cell carcinoma. N Engl J Med 335:865–875PubMedCrossRef

Nachmias B, Ashhab Y, Ben-Yehuda D (2004) The inhibitor of apoptosis protein family (IAPs): an emerging therapeutic target in cancer. Semin Cancer Biol 14:231–243PubMedCrossRef

Nunez G, Benedict MA, Hu Y, Inohara N (1998) Caspases: the proteases of the apoptotic pathway. Oncogene 17:3237–3245PubMedCrossRef

Pantuck AJ, Zisman A, Belldegrun AS (2001) The changing natural history of renal cell carcinoma. J Urol 166:1611–1623PubMedCrossRef

Rabinovitch RA, Zelefsky MJ, Gaynor JJ, Fuks Z (1994) Patterns of failure following surgical resection of renal cell carcinoma: implications for adjuvant local and systemic therapy. J Clin Oncol 12:206–212PubMed

Reed JC (1999) Dysregulation of apoptosis in cancer. J Clin Oncol 17:2941–2953PubMed

Salvesen GS, Duckett CS (2002) IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol 3:401–410PubMedCrossRef

Sandock DS, Seftel AD, Resnick MI (1995) A new protocol for the follow-up of renal cell carcinoma based on pathological stage. J Urol 154:28–31PubMedCrossRef

Sekimura A, Konishi A, Mizuno K, Kobayashi Y, Sasaki H, Yano M, Fukai I, Fujii Y (2004) Expression of Smac/DIABLO is a novel prognostic marker in lung cancer. Oncol Rep 11:797–802PubMed

Silke J, Hawkins CJ, Ekert PG, Chew J, Day CL, Pakusch M, Verhagen AM, Vaux DL (2002) The anti-apoptotic activity of XIAP is retained upon mutation of both the caspase 3- and caspase 9-interacting sites. J Cell Biol 157:115–124PubMedCrossRef

Song Z, Yao X, Wu M (2003) Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis. J Biol Chem 278:23130–23140PubMedCrossRef

Tsui KH, Shvarts O, Smith RB, Figlin RA, deKernion JB, Belldegrun A (2000) Prognostic indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the revised 1997 TNM staging criteria. J Urol 163:1090–1095, quiz 1295PubMedCrossRef

Verhagen AM, Vaux DL (2002) Cell death regulation by the mammalian IAP antagonist DIABLO/Smac. Apoptosis 7:163–166PubMedCrossRef

Vucic D, Deshayes K, Ackerly H, Pisabarro MT, Kadkhodayan S, Fairbrother WJ, Dixit VM (2002) SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP). J Biol Chem 277:12275–12279PubMedCrossRef

Wilkinson JC, Wilkinson AS, Scott FL, Csomos RA, Salvesen GS, Duckett CS (2004) Neutralization of Smac/DIABLO by inhibitors of apoptosis (IAPs). A caspase-independent mechanism for apoptotic inhibition. J Biol Chem 279:51082–51090PubMedCrossRef

Xie W, Jiang P, Miao L, Zhao Y, Zhimin Z, Qing L, Zhu WG, Wu M (2006) Novel link between E2F1 and Smac/DIABLO: proapoptotic Smac/DIABLO is transcriptionally upregulated by E2F1. Nucleic Acids Res 34:2046–2055PubMedCrossRef

Yan Y, Mahotka C, Heikaus S, Shibata T, Wethkamp N, Liebmann J, Suschek CV, Guo Y, Gabbert HE, Gerharz CD, Ramp U (2004) Disturbed balance of expression between XIAP and Smac/DIABLO during tumour progression in renal cell carcinomas. Br J Cancer 91:1349–1357PubMedCrossRef

Yoo NJ, Kim HS, Kim SY, Park WS, Park CH, Jeon HM, Jung ES, Lee JY, Lee SH (2003) Immunohistochemical analysis of Smac/DIABLO expression in human carcinomas and sarcomas. APMIS 111:382–388PubMedCrossRef

Zisman A, Pantuck AJ, Dorey F, Said JW, Shvarts O, Quintana D, Gitlitz BJ, deKernion JB, Figlin RA, Belldegrun AS (2001) Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol 19:1649–1657PubMed

Title: Expression levels of the mitochondrial IAP antagonists Smac/DIABLO and Omi/HtrA2 in clear-cell renal cell carcinomas and their prognostic value
Authors: Carsten Kempkensteffen
Stefan Hinz
Frank Christoph
Hans Krause
Ahmed Magheli
Mark Schrader
Martin Schostak
Kurt Miller
Steffen Weikert
Publication date: 01-05-2008
Publisher: Springer-Verlag
Published in: Journal of Cancer Research and Clinical Oncology / Issue 5/2008
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-007-0317-7

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 5/2008

APC promoter methylation and protein expression in hepatocellular carcinoma

Low nuclear grade but not cell proliferation predictive of pathological complete response to docetaxel in human breast cancers

Enhancement of dendritic cell-tumor fusion vaccine potency by indoleamine-pyrrole 2,3-dioxygenase inhibitor, 1-MT

Overexpression of cFLIP in head and neck squamous cell carcinoma and its clinicopathologic correlations

Increased polycomb-group oncogene Bmi-1 expression correlates with poor prognosis in hepatocellular carcinoma

Stat3 up-regulates expression of nicotinamide N-methyltransferase in human cancer cells

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials