Knockdown of CRM1 inhibits the nuclear export of p27Kip1 phosphorylated at serine 10 and plays a role in the pathogenesis of epithelial ovarian cancer

Wang, You; Wang, Yingying; Xiang, Jun; Ji, Fang; Deng, Yan; Tang, Chunhui; Yang, Shuyun; Xi, Qinghua; Liu, Rong; Di, Wen

doi:10.1016/j.canlet.2013.09.002

Cited by 45 publications

(43 citation statements)

References 18 publications

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“…Signaling pathways, such as PI3K-AKT and MAPK, are known to play roles in such modifications (8), and aberrant activation of these pathways can lead to mislocalization and functional alterations of several TSPs, including cyclin-dependent kinase inhibitor 1A (CDKN1A and p21 Cip1 ), CDK inhibitor 1B (CDKN1B and p27 Kip1 ), forkhead box O (FOXO) proteins, and TP53 (7). The CDKN1A and CDKN1B act as tumor suppressors in the nucleus through inhibition of cyclin-dependent kinases (CDK) during cell-cycle progression (9,10). However, they may acquire oncogenic properties when mislocalized in the cytoplasm, leading to increased cell migration and invasion through the inhibition of Rho proteins and their effector Rho-kinase (11,12).…”

Section: Oncogenic Signaling Pathways and Dysregulated Nucleocytoplasmentioning

confidence: 99%

“…However, they may acquire oncogenic properties when mislocalized in the cytoplasm, leading to increased cell migration and invasion through the inhibition of Rho proteins and their effector Rho-kinase (11,12). Phosphorylation of CDKN1A by AKT and PKC inhibits CDKN1A nuclear import, whereas CDKN1B phosphorylation by AKT and ERK enhances CDKN1B nuclear export, thereby contributing to their inappropriate cytoplasmic localization (10)(11)(12). Such mislocalization has been observed in esophageal, thyroid, colon, breast, and ovarian cancers, and is related to higher histologic grade, advanced stage of disease, and poorer patient survival (9)(10)(11)(12).…”

Section: Oncogenic Signaling Pathways and Dysregulated Nucleocytoplasmentioning

confidence: 99%

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Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

Conforti

Wang

Rodriguez

et al. 2015

Clinical Cancer Research

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A dynamic distribution between nucleus and cytoplasm (nucleocytoplasmic shuttling) is one of the control mechanisms adapted by normal cells to regulate the activity of a variety of molecules. Growing evidence suggests that dysregulation of the nucleocytoplasmic shuttling is involved in promoting abnormal cell survival, tumor progression, and drug resistance, and is associated with poor cancer prognosis. Aberrant nucleocytoplasmic shuttling in cancer cells may result from a hyperactive status of diverse signal-transduction pathways, such as the PI3K-AKT and MAPK pathways, or from alterations in the general nuclear import/export machinery. Among the large number of molecules involved in the shuttling process, exportin XPO1, also known as chromosome region maintenance 1, appears to play a particularly prominent role in pathogenesis of both hematological malignancies and solid tumors. Given the importance of nucleocytoplasmic shuttling in cancer pathogenesis and the rapidly expanding knowledge in this field, attempts have been made to develop compounds able to revert the aberrant nucleocytoplasmic shuttling. A promising new drug, , which belongs to the class of XPO1 inhibitors called selective inhibitors of nuclear export, is now being tested in phase I/II clinical trials.

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Section: Oncogenic Signaling Pathways and Dysregulated Nucleocytoplasmentioning

confidence: 99%

Section: Oncogenic Signaling Pathways and Dysregulated Nucleocytoplasmentioning

confidence: 99%

Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

Conforti

Wang

Rodriguez

et al. 2015

Clinical Cancer Research

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“…The increase in CRM1 leads to cytoplasmic abundance of tumor suppressors and cell cycle regulators, which in turn results in their aberrant activation. Knock-down of CRM1 expression prevents nuclear export of p27, resulting in cell cycle arrest [65] . Specific suppression of CRM1 caused nuclear retention of p21 and induced apoptosis [66] .…”

Section: Future Perspectivementioning

confidence: 99%

Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy

Ohkoshi

Yano

Matsuda

2015

WJG

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A well-known tumor suppressor, p21, acts paradoxically by promoting tumor growth in some cellular conditions. These conflicting functions have been demonstrated in association with the HBx gene and in hepatocarcinogenesis. The molecular behavior of p21 depends on its subcellular localization. Nuclear p21 may inhibit cell proliferation and be proapoptotic, while cytoplasmic p21 may have oncogenic and anti-apoptotic functions. Because most typical tumor suppressive proteins also have different effects according to subcellular localization, elucidating the regulatory mechanisms underlying nucleo-cytoplasmic transport of these proteins would be significant and may lead to a new strategy for anti-hepatocellular carcinoma (HCC) therapy. Chromosome region maintenance 1 (CRM1) is a major nuclear export receptor involved in transport of tumor suppressors from nucleus to cytoplasm. Expression of CRM1 is enhanced in a variety of malignancies and in vitro studies have shown the efficacy of specific inhibition of CRM1 against cancer cell lines. Interestingly, interferon may keep p21 in the nucleus; this is one of the mechanisms of its anti-hepatocarcinogenic function. Here we review the oncogenic property of p21, which depends on its subcellular localization, and discuss the rationale underlying a new strategy for HCC treatment and prevention. Core tip: A well-known tumor suppressor, p21, can act paradoxically by promoting tumor growth, depending on its subcellular localization. Nuclear p21 may inhibit cell proliferation while cytoplasmic p21 may be associated with anti-apoptotic and oncogenic functions. REVIEW

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“…Cytoplasmic localization of p27 has been observed in esophageal, thyroid, colon, and breast cancers ( 3 ). Wang and colleagues ( 52 ) recently demonstrated that increased XPO1 and phosphorylated Ser10 p27 (pSer10p27) expression levels were associated with advanced-stage and high-grade epithelial ovarian cancer and poorer overall survival. Knockdown of XPO1 and pSer10p27 expression levels also leads to cell-cycle arrest and inhibition of cell proliferation in SKOV3 cells in vitro and in vivo ( 52 ).…”

Section: Reviewmentioning

confidence: 99%

Promising SINEs for Embargoing Nuclear–Cytoplasmic Export as an Anticancer Strategy

et al. 2014

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In cancer cells, the nuclear-cytoplasmic transport machinery is frequently disrupted, resulting in mislocalization and loss of function for many key regulatory proteins. In this review, the mechanisms by which tumor cells co-opt the nuclear transport machinery to facilitate carcinogenesis, cell survival, drug resistance, and tumor progression will be elucidated, with a particular focus on the role of the nuclear-cytoplasmic export protein. The recent development of a new generation of selective inhibitors of nuclear export (XPO1 antagonists) and how these novel anticancer drugs may bring us closer to the implementation of this therapeutic strategy in the clinic will be discussed. Signifi cance:The nuclear transport mechanism is dysregulated in many malignancies and is associated with dysfunction of many regulatory proteins. Targeting this mechanism as an anticancer strategy has been compelling, and novel agents that selectively inhibit the nuclear export pathway have demonstrated preliminary evidence of clinical effi cacy with an acceptable safety profi le. Cancer Discov; 4(5); 527-37.

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Knockdown of CRM1 inhibits the nuclear export of p27Kip1 phosphorylated at serine 10 and plays a role in the pathogenesis of epithelial ovarian cancer

Cited by 45 publications

References 18 publications

Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy

Promising SINEs for Embargoing Nuclear–Cytoplasmic Export as an Anticancer Strategy

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