Nuclear cIAP1 overexpression is a tumor stage- and grade-independent predictor of poor prognosis in human bladder cancer patients

Che, Xiangyu; Yang, Deyong; Zong, Hong; Wang, Jianbo; Li, Xiancheng; Chen, Feng; Chen, Xiaochi; Song, Xishuang

doi:10.1016/j.urolonc.2010.12.016

Cited by 39 publications

(36 citation statements)

References 26 publications

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“…Nuclear cIAP1 overexpression is associated with poor prognosis in bladder cancer, lymph node metastasis and head and neck squamous cell carcinoma patients 47, 48. We found that nuclear cIAP1 expression is much higher in MB cells relative to normal brain tissues, and inversely correlates nuclear p21 expression (Figure 7).…”

Section: Discussionmentioning

confidence: 71%

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

et al. 2018

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Medulloblastoma (MB) is the most common type of malignant childhood brain tumor. We previously showed that inhibitors of apoptosis proteins (IAP) small‐molecule inhibitors (LCL161 or LBW242) combined with chemotherapy have synergistic antiproliferative effects on MB cells. The synergistic antitumor effects of combination treatments happen through induction of autophagy and caspase‐3/7‐activated apoptosis. Here, we investigated the effects of IAP inhibitors or silencing IAP on cell cycle regulation. We discovered that treatment with IAP inhibitors or their combination with conventional chemotherapy (vincristine or cisplatin), as well as RNAi knockdown of cIAP1/2 or XIAP arrested MB cells in the G2/M phase through downregulation of cyclin B1‐CDK1 and cyclin A‐CDK1/2. Among these three IAPs, only silencing cIAP1 expression enhanced p21 dependent‐G2/M phase accumulation. IAP inhibitors reduced cIAP1 expression and increased p21 expression in time course experiments. Furthermore, cIAP1 can govern p21 proteasomal degradation via neddylation in lieu of ubiquitination. Inhibition of IAPs significantly abrogated cIAP1‐mediated p21 degradation. We also observed an inverse correlation between nuclear cIAP1 and nuclear p21 expressions in MB tumor tissues. These findings provide new mechanistic evidence of the influence of IAP inhibitors on MB cell proliferation through disruption of the cell cycle.

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Section: Discussionmentioning

confidence: 71%

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

et al. 2018

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“…To our knowledge, until now, there have been no studies determining the role of these proteins in breast cancer. High expression of cIAP-1 and cIAP-2 was found to be a poor prognostic factor in bladder cancer patients, where expression of cIAP-1 and cIAP-2 strongly correlates with tumor stage, tumor grade, tumor recurrence and tumor related death [35]. On the other hand, downregulation of cIAP-1 was connected with an unfavorable outcome in renal cell carcinoma [36], all of which may indicate that the function of cIAP-1 and cIAP-2 and their role in cancer behavior depend on tumor type.…”

Section: Discussionmentioning

confidence: 99%

Expression of IAP family proteins and its clinical importance in breast cancer patients

Pluta¹,

Jeziorski²,

Cebula-Obrzut³

et al. 2015

neo

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Inhibitor of apoptosis (IAP) family proteins is involved in mechanisms of resistance to apoptosis in various cancer cells. The aim of this study was to assess the expression of selected IAP proteins such as XIAP, cIAP-1, cIAP-2 and survivin in breast cancer patients and evaluates their relationship with the prognostic and predictive factors and their impact to overall survival (OS) and progression free survival (PFS). The study was conducted with the use of tissue samples prospectively collected from 92 previously untreated female breast cancer patients. The control encompassed 10 fibroadenoma patients. The expression of XIAP, cIAP-1, cIAP-2 and survivin was assessed using flow multicolor cytometry. XIAP expression was present in 99 % of the breast cancer patients (91/92) with the median expression 13.65% (range 1-66.8%). Expression of XIAP in breast cancer was significantly higher compared to the control group (p=0.006). Median expression of cIAP-1, cIAP-2 and survivin in the study group was 25.95% (range 0.8-83.7%), 16.7% (range 1-53.2%) and 4.6% (range 0-43%) respectively. In the rank Spearman test, strong correlations (p<0.001) were seen among the expressions of XIAP, cIAP-2 and survivin, in all combination. Additionally, week correlation between XIAP and cIAP-1 was observed (p=0.02). The median expression of XIAP and survivin was significantly higher in more advanced tumors (stages pT2/pT3 vs. pT1). The median PFS and OS in breast cancer group were 46.15 and 47.1 months respectively. No significant correlations were observed among expressions of IAP family proteins and survival. However, low expression of XIAP in breast cancer showed trend to longer PFS (p=0.08). XIAP, cIAP-1 cIAP-2 and survivin participate in antiapoptotic mechanisms in breast cancer and XIAP and survivin seem to have the most significant prognostic importance. Further studies are needed to establish more complete prognostic and predictive values of IAP family proteins in breast cancer patients.

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“…c-IAPs, XIAP and melanoma IAP bind caspase-3, −7 and −9 via the BIR domains (37–40), and induce their ubiquitination or neddylation via the RING domain (41,42). Moreover, c-IAPs are positive regulators of cell proliferation (43), and the nuclear expression of c-IAP1 has been associated with advanced disease stages and poor patient prognosis in human cervical and esophageal squamous cell carcinomas and bladder cancers (44–46). To date, the overexpression of several IAPs has been detected in various cancers including NSCLC (22–24,27,47), and IAPs are significant targets for therapeutic intervention.…”

Section: Discussionmentioning

confidence: 99%

Osthole induces lung cancer cell apoptosis through inhibition of inhibitor of apoptosis family proteins

Zhang

et al. 2016

Oncology Letters

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In the present study, we investigated the effects and mechanisms of Osthole on the apoptosis of non-small cell lung cancer (NSCLC) cells and its synergistic effect with Embelin. Our results revealed that treatment with both Osthole and Embelin inhibited cell proliferation. Notably, combination treatment of Osthole and Embelin inhibited cell proliferation more significantly compared with monotherapy. In addition, morphological analysis and Annexin V/propidium iodide analysis revealed that the combination of Osthole and Embelin enhanced their effect on cell apoptosis. We further examined the effect of Osthole on the expression of inhibitor of apoptosis protein (IAP) family proteins. That treatment of A549 lung cancer cells with various concentrations of Osthole was observed to decrease the protein expression of X-chromosome-encoded IAP, c-IAP1, c-IAP2 and Survivin, and increase Smac expression in a dose-dependent manner. Furthermore, it was noted that Osthole or Embelin alone increased the expression of BAX, caspase-3, caspase-9, cleaved caspase-3 and cleaved caspase-9, and decreased Bcl-2 levels following treatment. Osthole and Embelin combination treatment had a synergistic effect on the regulation of these proteins. In conclusion, our study demonstrated that Osthole inhibited proliferation and induced the apoptosis of lung cancer cells via IAP family proteins in a dose-dependent manner. Osthole enhances the antitumor effect of Embelin, indicating that combination of Osthole and Embelin has potential clinical significance in the treatment of NSCLC.

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Nuclear cIAP1 overexpression is a tumor stage- and grade-independent predictor of poor prognosis in human bladder cancer patients

Cited by 39 publications

References 26 publications

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

Expression of IAP family proteins and its clinical importance in breast cancer patients

Osthole induces lung cancer cell apoptosis through inhibition of inhibitor of apoptosis family proteins

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