Expression of Crm1 in Human Gliomas and Its Significance in P27 Expression and Clinical Prognosis

Shen, Aiguo; Wang, Yuchan; Zhao, Yueming; Zou, Lin; Sun, Linlin; Cheng, Chun

doi:10.1227/01.neu.0000348550.47441.4b

Cited by 160 publications

(142 citation statements)

References 26 publications

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“…Mechanistically, overexpression of XPO1 enhances export of nuclear tumor suppressor proteins such as p53, BRCA1, allophycocyanin, and NMP1, resulting in drug resistance. 33 Overexpression of XPO1 has also been associated with drug resistance and poor outcome in many solid tumors such as glioblastoma, cervical and ovarian cancer, [35][36][37] and various hematologic malignancies, including myeloma, 38 chronic lymphocytic leukemia, 26 T-cell acute lymphoblastic leukemia, acute myeloid leukemia, [39][40][41] and BCR-ABL1-driven blastic transformation. 19,42 In the shRNA library screen, shRAN-infected cells were depleted by fourfold in K562 R compared with K562 S cells (supplemental Table 4) following 9 days in culture.…”

Section: Discussionmentioning

confidence: 99%

shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance

Khorashad

Eiring

Mason

et al. 2015

Blood

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The mechanisms underlying tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML) patients lacking explanatory BCR-ABL1 kinase domain mutations are incompletely understood. To identify mechanisms of TKI resistance that are independent of BCR-ABL1 kinase activity, we introduced a lentiviral short hairpin RNA (shRNA) library targeting ∼5000 cell signaling genes into K562 R , a CML cell line with BCR-ABL1 kinaseindependent TKI resistance expressing exclusively native BCR-ABL1. A customized algorithm identified genes whose shRNA-mediated knockdown markedly impaired growth of K562 R cells compared with TKI-sensitive controls. Among the top candidates were 2 components of the nucleocytoplasmic transport complex, RAN and XPO1 (CRM1). shRNA-mediated RAN inhibition or treatment of cells with the XPO1 inhibitor, KPT-330 (Selinexor), increased the imatinib sensitivity of CML cell lines with kinase-independent TKI resistance. Inhibition of either RAN or XPO1 impaired colony formation of CD34 1 cells from newly diagnosed and TKI-resistant CML patients in the presence of imatinib, without effects on CD34 1 cells from normal cord blood or from a patient harboring the BCR-ABL1 T315I mutant. These data implicate RAN in BCR-ABL1 kinase-independent imatinib resistance and show that shRNA library screens are useful to identify alternative pathways critical to drug resistance in CML. (Blood. 2015;125(11):1772-1781

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Section: Discussionmentioning

confidence: 99%

shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance

Khorashad

Eiring

Mason

et al. 2015

Blood

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“…8,9 Thus, XPO1 inhibition may result in increased levels of active TSP, and orally bioavailable selective inhibitors of nuclear export (SINE) that covalently bind and inhibit XPO1 are being explored as a novel therapeutic approach in solid tumors and hematologic malignancies.…”

Section: 3mentioning

confidence: 99%

Decitabine priming enhances the antileukemic effects of exportin 1 (XPO1) selective inhibitor selinexor in acute myeloid leukemia

Ranganathan

Santhanam

et al. 2015

Blood

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• Decitabine priming increases antileukemic effects of selinexor in AML in vitro and in vivo.• Decitabine priming allows for decreasing the dose of selinexor in patients, thus increasing tolerability without affecting antileukemic activity.The prognosis of acute myeloid leukemia (AML) is poor, highlighting the need for novel treatments. Hypomethylating agents, including decitabine are used to treat elderly AML patients with relative success. Targeting nuclear export receptor (exportin 1 [XPO1]) is a novel approach to restore tumor suppressor (TS) function in AML. Here, we show that sequential treatment of AML blasts with decitabine followed by selinexor (XPO1 inhibitor) enhances the antileukemic effects of selinexor. These effects could be mediated by the reexpression of a subset of TSs (CDKN1A and FOXO3A) that are epigenetically silenced via DNA methylation, and cytoplasmic-nuclear trafficking is regulated by XPO1. We observed a significant upregulation of CDKN1A and FOXO3A in decitabine-versus control-treated cells. Sequential treatment of decitabine followed by selinexor in an MV4-11 xenograft model significantly improved survival compared with selinexor alone. On the basis of these preclinical results, a phase 1 clinical trial of decitabine followed by selinexor in elderly patients with AML has been initiated. (Blood. 2015;125(17):2689-2692) IntroductionAcute myeloid leukemia (AML) is a clonal hematopoietic disorder characterized by genetic and epigenetic alterations leading to a block in differentiation and accumulation of leukemic blasts in blood and bone marrow (BM). 1 Epigenetic silencing of genes involved in hematopoietic differentiation plays a critical role in myeloid leukemogenesis. 2,3Gene silencing caused by DNA hypermethylation can be reversed pharmacologically by inhibition of DNA methyltransferases (DNMTs) using azanucleosides such as decitabine.2,3 Our group recently reported a 47% complete response rate with a 10-day regimen of lowdose decitabine as a single agent in previously untreated older AML patients (.60 years). 4 Although patients' survival was not significantly better than that obtained with more intensive chemotherapy regimens (ie, 7 1 3), the single-agent decitabine regimen was well tolerated and had low toxicity. These results therefore suggest the opportunity to capitalize on this relatively nontoxic treatment and make it more effective by incorporating this compound into novel molecularly targeted approaches. Exportin 1 (XPO1) is a nuclear exporter involved in the active transport of a number of cargo proteins, including transcription factors and tumor suppressor proteins (TSPs; ie, p53 and p27), cell-cycle regulators (ie, Cdkn1a), and RNA molecules. 5,6 Recent data indicate that TSP can be exported from the nucleus and thereby inactivated in cancer by hyperactive nuclear export.7 Indeed, XPO1 overexpression has been reported in several solid tumors and leukemias, including AML, and it is associated with worse outcome. 8,9 Thus, XPO1 inhibition may result in increased levels of a...

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“…CRM-1 expression has been found to correlate with a more aggressive tumor status and it has been suggested that CRM-1 may have prognostic value in gliomas, osteosarcomas, ovarian cancers and pancreatic cancers (18,20,32,33). Previous studies have also demonstrated an association between CRM-1 expression and resistance to chemotherapy and thus, potent inhibitors of CRM-1 are currently being developed for use in cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Expression of chromosomal regional maintenance protein-1 may be associated with subcellular survivin expression in human gastric and colorectal carcinoma

et al. 2016

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Abstract. Survivin, a member of the inhibitor of apoptosis protein family, is a potential prognostic marker and molecular target for anticancer therapies. Chromosomal regional maintenance protein-1 (CRM-1) mediates the nuclear export of proteins such as survivin. The aims of the present study were to compare the expression and subcellular localization of CRM-1 in human gastric and colorectal carcinomas and to assess the association between CRM-1 and survivin expression in these tumor types. The nuclear and cytoplasmic CRM-1 expression rates in gastric carcinoma were 61% (42/69) and 29% (20/69), respectively, while the nuclear and cytoplasmic CRM-1 expression rates in colorectal carcinoma were 55% (43/78) and 37% (29/78), respectively. Nuclear and cytoplasmic CRM-1 expression was found to be significantly correlated with nuclear and cytoplasmic survivin expression in colorectal carcinoma, but not gastric carcinoma. These results indicate that CRM-1 expression patterns differ between gastric and colorectal carcinomas and thus, we hypothesize that CRM-1-mediated nuclear export of survivin may be deregulated in gastric carcinoma. Therefore, CRM-1 may exhibit different functions in gastric and colorectal carcinoma.

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Expression of Crm1 in Human Gliomas and Its Significance in P27 Expression and Clinical Prognosis

Abstract: The current results showed that CRM1 and p27 expression were associated with glioma grade and that high CRM1 protein expression might be related to poor outcome.

Cited by 160 publications

References 26 publications

shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance

shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance

Decitabine priming enhances the antileukemic effects of exportin 1 (XPO1) selective inhibitor selinexor in acute myeloid leukemia

Expression of chromosomal regional maintenance protein-1 may be associated with subcellular survivin expression in human gastric and colorectal carcinoma

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