Overexpression of XIAP expression in renal cell carcinoma predicts a worse prognosis

Mizutani, Yoichi; Nakanishi, Hiroyuki; Li, Yong Nan; Matsubara, Hiroki; Yamamoto, Kosuke; Sato, Nodoka; Shiraishi, Takeshi; Nakamura, Toshio; Mikami, Kōichi; Okihara, Koji; Takaha, Natsuki; Ukimura, Osamu; Kawauchi, Akihiro; Nonomura, Norio; Bonavida, Benjamin; Miki, Tsuneharu

doi:10.3892/ijo.30.4.919

Cited by 72 publications

(61 citation statements)

References 24 publications

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“…Increased expression of XIAP has been observed in many human cancers, including prostate, lung and acute/chronic leukemia (Ferreira et al, 2001;Krajewska et al, 2003;Schimmer et al, 2003). Furthermore, its expression has been correlated with a worse prognosis in bladder carcinoma, renal cell carcinoma and acute myloid leukemia (Tamm et al, 2004;Li et al, 2007;Mizutani et al, 2007). Earlier studies have shown that HCT116 or DLD-1 cells in which XIAP expression has been downregulated exhibit increased caspase 3 cleavage and apoptosis in response to TRAIL (Cummins et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

et al. 2008

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Death receptors can directly (type I cells) or indirectly induce apoptosis by activating mitochondrial-regulated apoptosis (type II cells). The level of caspase 8 activation is thought to determine whether a cell is type I or II, with type II cells less efficient at activating this caspase following death receptor activation. FLICE-inhibitory protein (FLIP) blocks death receptor-mediated apoptosis by inhibiting caspase 8 activation; therefore, we assessed whether silencing FLIP could convert type II cells into type I. FLIP silencing-induced caspase 8 activation in Bax wild-type and null HCT116 colorectal cancer cells; however, complete caspase 3 processing and apoptosis were only observed in Bax wild-type cells. Bax-null cells were also more resistant to chemotherapy and tumor necrosis factor-related apoptosis inducing ligand and, unlike the Bax wild-type cells, were not sensitized to these agents by FLIP silencing. Further analyses indicated that release of second mitochondrial activator of caspases from mitochondria and subsequent inhibition of X-linked inhibitor of apoptosis protein (XIAP) was required to induce full caspase 3 processing and apoptosis following FLIP silencing. These results indicate that silencing FLIP does not necessarily bypass the requirement for mitochondrial involvement in type II cells. Furthermore, targeting FLIP and XIAP may represent a therapeutic strategy for the treatment of colorectal tumors with defects in mitochondrial-regulated apoptosis.

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Section: Discussionmentioning

confidence: 99%

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

et al. 2008

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“…Elevated expression of XIAP has been demonstrated in cancers of various origins. [10][11][12][13][14][15][16] Not only is XIAP overexpressed in cancer, increased XIAP expression has been shown to contribute to apoptosis resistance and conversely, XIAP antagonism sensitizes cancer cells to multiple types of apoptotic stimuli in vitro and in vivo. 13,[17][18][19][20][21][22][23][24][25]28,[32][33][34][35][36][37] These apoptotic stimuli have included various chemotherapeutic agents, ionizing radiation, tumor necrosis factor-related apoptosis-inducing ligand, anoikis induction and immune clearance by cytotoxic lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

“…21,[23][24][25] Consistent with an antiapoptotic role, high levels of XIAP have an adverse prognosis in certain cancers. 14,15 However, there was an unexpected favorable prognosis seen in prostate and non-small cell lung cancers with high levels of XIAP expression. 12,26 We thus chose to further examine the role of XIAP in a tumor model that would resemble human cancer more closely than xenograft or in vitro studies.…”

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confidence: 99%

“…[7][8][9] XIAP overexpression has been reported in a variety of human cancers. [10][11][12][13][14][15][16] Increased XIAP levels have been linked to escaping anoikis and apoptosis induced by radiation, chemotherapy and death receptor ligands. 13,[17][18][19][20][21][22] Furthermore, antagonism of XIAP has been reported to have antitumor activity in a number of models, including prostate cancer.…”

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X-linked inhibitor of apoptosis deficiency in the TRAMP mouse prostate cancer model

et al. 2008

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Deregulation of apoptotic pathways plays a central role in cancer pathogenesis. X-linked inhibitor of apoptosis protein (XIAP), is an antiapoptotic molecule, whose elevated expression has been observed in tumor specimens from patients with prostate carcinoma. Studies in human cancer cell culture models and xenograft tumor models have demonstrated that loss of XIAP sensitizes cancer cells to apoptotic stimuli and abrogates tumor growth. In view of these findings, XIAP represents an attractive antiapoptotic therapeutic target for prostate cancer. To examine the role of XIAP in an immunocompetent mouse cancer model, we have generated transgenic adenocarcinoma of the mouse prostate (TRAMP) mice that lack XIAP. We did not observe a protective effect of Xiap deficiency in TRAMP mice as measured by tumor onset and overall survival. In fact, there was an unexpected trend toward more aggressive disease in the Xiap-deficient mice. These findings suggest that alternative mechanisms of apoptosis resistance are playing a significant oncogenic role in the setting of Xiap deficiency. Our study has implications for XIAP-targeting therapies currently in development. Greater understanding of these mechanisms will aid in combating resistance to XIAP-targeting treatment, in addition to optimizing selection of patients who are most likely to respond to such treatment. Cell Death and Differentiation (2008) Apoptosis is a process of cell death that is tightly regulated by a cadre of both pro-and antiapoptotic proteins. In contrast to healthy cells, a hallmark of cancerous cells is the acquired capacity to evade this process of programmed cell death. 1,2 The acquisition of genetic lesions leading to oncogene activation normally triggers a program of apoptosis or senescence. Additionally, the tumor microenvironment often exposes malignant cells to apoptotic stimuli, such as hypoxia or activation of death receptors. Thus, suppression of the pathway leading to cell death has been suggested as a necessarily early event in the development of neoplasia.Execution of the apoptotic cell death process is carried out by caspases, a family of cysteine aspartate proteases. 3,4 During apoptosis, loss of mitochondrial integrity or engagement of death receptors leads to the activation of initiator caspase-9 or -8, respectively. In either case, the initiator caspases cleave and activate effector caspases, including caspase-3 or -7. The cascade of caspase cleavage is regulated by X-linked inhibitor of apoptosis protein (XIAP). XIAP belongs to the IAP family, characterized by containing at least one zinc-binding baculovirus IAP repeat. 5 The only member of the IAP family that potently inhibits caspase activity, XIAP has been demonstrated to directly inhibit caspases-3, -7 and -9, blocking both intrinsic and extrinsic apoptotic signals. 6 Given its role in apoptosis, there has been much interest in understanding the role of XIAP in cancer and evaluating XIAP as a therapeutic target. [7][8][9] XIAP overexpression has been reported in a variety of human ca...

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“…[6][7][8][9][10][11] XIAP expression correlates with clinical aggressiveness in acute myelogenous leukemia, diffuse large B-cell lymphoma and renal cell carcinoma. [12][13][14] XIAP is expressed in some normal tissues; 15 however, XIAP-knockout mice lack any significant pathology, suggesting normal cells function properly in its absence. For all of the above reasons, XIAP is considered an attractive target for drug discovery.…”

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confidence: 99%

Immunohistochemical detection of XIAP and p63 in adenomatous hyperplasia, atypical adenomatous hyperplasia, bronchioloalveolar carcinoma and well-differentiated adenocarcinoma

Orta

Gil

et al. 2008

Modern Pathology

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The critical distinction of bronchioloalveolar carcinoma (BAC), well-differentiated adenocarcinoma (WDAC) of lung, adenomatous hyperplasia (AH) and atypical adenomatous hyperplasia (AAH), is based on morphological criteria alone, and is therefore potentially subjective. We examined expression of two markers, X-linked inhibitor of apoptosis protein (XIAP), the most potent of the inhibitor of apoptosis protein (IAP) family, and p63, a marker of bronchial reserve cells (BRC) and squamous cells, in these entities. H&E slides of 37 tissue blocks from 27 patients were reviewed and classified as AH (n ¼ 7), AAH (n ¼ 8), BAC (n ¼ 9) and WDAC (n ¼ 13). Immunostaining was performed on 4 lm sections with monoclonal anti-XIAP and monoclonal anti-p63. Granular or heterogeneous cytoplasmic staining for XIAP and nuclear staining for p63 were considered positive. Neither XIAP nor p63 were detected in normal lung alveolar cells. All seven AHs were negative for XIAP and negative or focally positive for p63. All eight AAHs were positive for XIAP and displayed p63 positivity in scattered cells. All BACs displayed XIAP positivity, which ranged from focal/weak to diffuse/strong. p63 was negative in seven and focally positive in two of nine BACs. Twelve of 13 WDACs showed XIAP positivity in a similar pattern to BAC; all were negative for p63. One aberrant case diagnosed on H & E as WDAC was negative for XIAP but strongly positive for p63. Significant XIAP expression appears to be useful for distinguishing AAH from AH. Commonality of XIAP staining in AAH, BAC and WDAC supports the possibility that AAH may be a premalignant lesion. The rarity of p63 expression confirms previous reports and supports a nonbronchial histogenesis of these entities. In contrast, diffuse p63 staining may facilitate the identification of rare cases that may have been misclassified as alveolar in origin based on morphology but may be of BRC origin.

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Overexpression of XIAP expression in renal cell carcinoma predicts a worse prognosis

Cited by 72 publications

References 24 publications

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

X-linked inhibitor of apoptosis deficiency in the TRAMP mouse prostate cancer model

Immunohistochemical detection of XIAP and p63 in adenomatous hyperplasia, atypical adenomatous hyperplasia, bronchioloalveolar carcinoma and well-differentiated adenocarcinoma

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