Expression of the IAP protein family is dysregulated in pancreatic cancer cells and is important for resistance to chemotherapy

Lopes, Rita; Gangeswaran, Rathi; McNeish, Iain A.; Wang, Yaohe; Lemoine, Nick R.

doi:10.1002/ijc.22554

Cited by 133 publications

(109 citation statements)

References 43 publications

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“…Our results were consistent with this. Biological prediction and the apoptosis resistance function of XIAP in many tumors helped identify XIAP as target gene of miR-7 [19][20][21][22]. In our study, the loss of XIAP function showed growth suppression and apoptosis promotion in HeLa and C-33A cells, which is consistent with the results of miR-7 overexpression.…”

Section: Discussionsupporting

confidence: 87%

“…Thus, we chose XIAP for further study. XIAP has been demonstrated to be highly expressed in several malignancies, including cervical cancer, and plays an important role in regulating both apoptosis and cell proliferation [19][20][21][22]. The purpose of this study was to determine the effect of miR-7 on the malignant behaviors of cervical cancer cells and to explore the possible mechanisms of the XIAP gene regulation by miR-7 in cervical cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA‐7 downregulates XIAP expression to suppress cell growth and promote apoptosis in cervical cancer cells

et al. 2013

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Edited by Tamas DalmayKeywords: microRNA microRNA-7 X-linked inhibitor of apoptosis protein Cell apoptosis Cervical cancer a b s t r a c t Our study demonstrated the functions of microRNA-7 (miR-7) in cervical cancer. The overexpression of miR-7 in the cervical cancer cell lines HeLa and C-33A suppressed cell viability and promoted cell apoptosis, whereas the inhibition of miR-7 had opposite effects. Furthermore, an oncogene, Xlinked inhibitor of apoptosis protein (XIAP), was identified as a new target of miR-7, and the ectopic expression of XIAP rescued the effects induced by miR-7 in HeLa and C-33A cells. These results indicate that miR-7 targeted and downregulated the oncogene XIAP to regulate the effect of miR-7 on apoptosis and malignant behaviors of HeLa and C-33A cells.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

MicroRNA‐7 downregulates XIAP expression to suppress cell growth and promote apoptosis in cervical cancer cells

et al. 2013

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“…As to the precise mechanism of how Livin downregulation enhances chemosensitivity, it remains to be further clarified, and, at present, it is mainly considered that the downregulation sensitizes cells to death induction via mitochondrial pathway or increases cell death induced by the death receptor pathway. 33,34 Our results suggest that 5-FU chemotherapy could be more effective in combination with RNAi-mediated knockdown of Livin expression.…”

Section: Discussionmentioning

confidence: 77%

Silencing Livin gene expression to inhibit proliferation and enhance chemosensitivity in tumor cells

et al. 2008

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Livin, a novel member of the human inhibitors of apoptosis protein (IAP) family, plays an important role in tumor progression and occurrence by inhibiting cell apoptosis. It is selectively expressed in the most common human neoplasms and appears to be involved in tumor cell resistance to chemotherapeutic agents. To investigate its possibility as a therapeutic target for human malignancies, we established two genetically different stable tumor cell lines (LoVo and SPCA-1) and RNA interference (RNAi) technique was employed to downregulate Livin expression in two human tumor cell lines. The specific downregulation of Livin expression in tumor cell lines significantly inhibited in vitro cell proliferation and in vivo tumorigenicity. Furthermore, Livin knockdown led to cell arrest in the G 1 /G 0 phase of cell cycle, eventual apoptosis and chemosensitivity enhancement in tumor cells. All these results indicate that RNAi-mediated downregulation of Livin expression can lead to potent antitumor activity and chemosensitizing effects in human cancers.

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“…[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.…”

mentioning

confidence: 99%

“…[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. 21,[23][24][25] Consistent with an antiapoptotic role, high levels of XIAP have an adverse prognosis in certain cancers.…”

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confidence: 99%

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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Expression of the IAP protein family is dysregulated in pancreatic cancer cells and is important for resistance to chemotherapy

Cited by 133 publications

References 43 publications

MicroRNA‐7 downregulates XIAP expression to suppress cell growth and promote apoptosis in cervical cancer cells

MicroRNA‐7 downregulates XIAP expression to suppress cell growth and promote apoptosis in cervical cancer cells

Silencing Livin gene expression to inhibit proliferation and enhance chemosensitivity in tumor cells

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

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