Sensitization of pancreatic carcinoma cells for γ-irradiation-induced apoptosis by XIAP inhibition

被引：54

作者：

Giagkousiklidis S. ^{[1
]}

Vellanki S.H. ^{[1
]}

Debatin K.-M. ^{[1
]}

Fulda S. ^{[1
,2
]}

机构：

[1] University Children's Hospital, Ulm

[2] University Children's Hospital, D-89075 Ulm

来源：

Oncogene | 2007年 / 26卷 / 49期

关键词：

Apoptosis; IAPs; Pancreatic cancer; Radiotherapy;

D O I：

10.1038/sj.onc.1210502

中图分类号：

学科分类号：

摘要：

Resistance of pancreatic cancer to current treatments including radiotherapy remains a major challenge in oncology and may be caused by defects in apoptosis programs. Since 'inhibitor of apoptosis proteins' (IAPs) block apoptosis at the core of the apoptotic machinery by inhibiting caspases, therapeutic modulation of IAPs could tackle a key resistance mechanism. Here, we report that targeting X-linked inhibitor of apoptosis (XIAP) by RNA-interference-mediated knockdown or overexpression of second mitochondria-derived activator of caspase significantly enhanced apoptosis and markedly reduced clonogenic growth of pancreatic carcinoma cells upon γ-irradiation. Analysis of signaling pathways revealed that antagonizing XIAP increased activation of caspase-2, -3, -8 and -9 and loss of mitochondrial membrane potential upon γ-irradiation. Interestingly, inhibition of caspases also reduced the cooperative effect of XIAP targeting and γ-irradiation to trigger mitochondrial perturbations, suggesting that XIAP controls a feedback mitochondrial amplification loop by regulating caspase activity. Importantly, our data demonstrate for the first time that small molecule XIAP inhibitors sensitized pancreatic carcinoma cells for γ-irradiation-induced apoptosis, whereas they had no effect on γ-irradiation-mediated apoptosis of non-malignant fibroblasts indicating some tumor specificity. In conclusion, targeting XIAP, for example by small molecules, is a promising novel approach to enhance radiosensitivity of pancreatic cancer that warrants further investigation. © 2007 Nature Publishing Group All rights reserved.

引用

页码：7006 / 7016

页数：10

共 28 条

[1]

Cao C., Mu Y., Hallahan D.E., Lu B., XIAP and survivin as therapeutic targets for radiation sensitization in preclinical models of lung cancer, Oncogene, 23, pp. 7047-7052, (2004)

[2]

Cummins J.M., Kohli M., Rago C., Kinzler K.W., Vogelstein B., Bunz F., X-linked inhibitor of apoptosis protein (XIAP) is a nonredundant modulator of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human cancer cells, Cancer Res, 64, pp. 3006-3008, (2004)

[3]

Fulda S., Debatin K.M., Therapeutic modulation of apoptosis in cancer therapy, Apoptosis and Cancer Therapy, pp. 849-861, (2006)

[4]

Fulda S., Debatin K.M., Extrinsic versus intrinsic apoptosis pathways in anti-cancer chemotherapy, Oncogene, 25, pp. 4798-4811, (2006)

[5]

Fulda S., Debatin K.M., Targeting inhibitor of apoptosis proteins (IAPs) for diagnosis and treatment of human diseases, Rec Patents Anti-Cancer Drug Disc, 1, pp. 81-90, (2006)

[6]

Fulda S., Sieverts H., Friesen C., Herr I., Debatin K.M., The CD95 (APO-1/Fas) system mediates drug-induced apoptosis in neuroblastoma cells, Cancer Res, 57, pp. 3823-3829, (1997)

[7]

Fulda S., Wick W., Weller M., Debatin K.M., Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo, Nat Med, 8, pp. 808-815, (2002)

[8]

Giagkousiklidis S., Vogler M., Westhoff M.A., Kasperczyk H., Debatin K.M., Fulda S., Sensitization for γ-irradiation-induced apoptosis by Smac, Cancer Res, 65, pp. 10502-10513, (2005)

[9]

Guo F., Nimmanapalli R., Paranawithana S., Wittman S., Griffin D., Bali P., Ectopic overexpression of second mitochondria-derived activator of caspases (Smac/DIABLO) or cotreatment with N-terminus of Smac/DIABLO peptide potentiates epothilone B derivative-(BMS 247550) and Apo-2L/TRAIL-induced apoptosis, Blood, 99, pp. 3419-3426, (2002)

[10]

Holcik M., Yeh C., Korneluk R.G., Chow T., Translational upregulation of X-linked inhibitor of apoptosis (XIAP) increases resistance to radiation induced cell death, Oncogene, 19, pp. 4174-4177, (2000)

← 1 2 3 →