This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Giagkousiklidis, S. Articles by Fulda, S. Search for Related Content PubMed PubMed Citation Articles by Giagkousiklidis, S. Articles by Fulda, S.

Sensitization for -Irradiation–Induced Apoptosis by Second Mitochondria-Derived Activator of Caspase

University Children's Hospital, Ulm, Germany

Requests for reprints: Simone Fulda, University Children's Hospital, Eythstr. 24, D-89075 Ulm, Germany. Phone: 49-731-5002-5980; Fax: 49-731-5002-6765; E-mail: simone.fulda{at}medizin.uni-ulm.de.

Resistance to current treatment regimens, such as radiation therapy, remains a major concern in oncology and may be caused by defects in apoptosis programs. Because inhibitor of apoptosis proteins (IAPs), which are expressed at high levels in many tumors, block apoptosis at the core of the apoptotic machinery by inhibiting caspases, therapeutic modulation of IAPs could target a key control point in resistance. Here, we report for the first time that full-length or mature second mitochondria-derived activator of caspase (Smac), an inhibitor of IAPs, significantly enhanced -irradiation–induced apoptosis and reduced clonogenic survival in neuroblastoma, glioblastoma, or pancreatic carcinoma cells. Notably, Smac had no effect on DNA damage/DNA repair, activation of nuclear factor-B, up-regulation of p53 and p21 proteins, or cell cycle arrest following -irradiation, indicating that Smac did not alter the initial damage and/or cellular stress response. Smac enhanced activation of caspase-2, caspase-3, caspase-8, and caspase-9, loss of mitochondrial membrane potential, and cytochrome c release on -irradiation. Inhibition of caspases also blocked -irradiation–induced mitochondrial perturbations, indicating that Smac facilitated caspase activation, which in turn triggered a mitochondrial amplification loop. Interestingly, mitochondrial perturbations were completely blocked by the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone or the relatively selective caspase-2 inhibitor N-benzyloxycarbonyl-Val-Asp-Val-Ala-Asp-fluoromethylketone, whereas caspase-8 or caspase-3 inhibitors only inhibited the increased drop of mitochondrial membrane potential provided by Smac, suggesting that caspase-2 was acting upstream of mitochondria after -irradiation. In conclusion, our findings provide evidence that targeting IAPs (e.g., by Smac agonists) is a promising strategy to enhance radiosensitivity in human cancers.

This article has been cited by other articles:

				M. Vogler, H. Walczak, D. Stadel, T. L. Haas, F. Genze, M. Jovanovic, U. Bhanot, C. Hasel, P. Moller, J. E. Gschwend, et al. Small Molecule XIAP Inhibitors Enhance TRAIL-Induced Apoptosis and Antitumor Activity in Preclinical Models of Pancreatic Carcinoma Cancer Res., March 15, 2009; 69(6): 2425 - 2434. [Abstract] [Full Text] [PDF]

				M. N. Uddin, D. Horvat, S. S. Glaser, B. M. Mitchell, and J. B. Puschett Examination of the Cellular Mechanisms by Which Marinobufagenin Inhibits Cytotrophoblast Function J. Biol. Chem., June 27, 2008; 283(26): 17946 - 17953. [Abstract] [Full Text] [PDF]

				D. S. Ziegler, A. L. Kung, and M. W. Kieran Anti-Apoptosis Mechanisms in Malignant Gliomas J. Clin. Oncol., January 20, 2008; 26(3): 493 - 500. [Abstract] [Full Text] [PDF]

				A. Bank, P. Wang, C. Du, J. Yu, and L. Zhang SMAC Mimetics Sensitize Nonsteroidal Anti-inflammatory Drug Induced Apoptosis by Promoting Caspase-3 Mediated Cytochrome c Release Cancer Res., January 1, 2008; 68(1): 276 - 284. [Abstract] [Full Text] [PDF]

				K. M. Greeneltch, M. Schneider, S. M. Steinberg, D. J. Liewehr, T. J. Stewart, K. Liu, and S. I. Abrams Host Immunosurveillance Controls Tumor Growth via IFN Regulatory Factor-8 Dependent Mechanisms Cancer Res., November 1, 2007; 67(21): 10406 - 10416. [Abstract] [Full Text] [PDF]