Upregulation of KPNβ1 in gastric cancer cell promotes tumor cell proliferation and predicts poor prognosis

Zhu, Jiang; Wang, Yingying; Huang, Hua; Yang, Qichang; Cai, Jing; Wang, Qiuhong; Gu, Xiaoling; Xu, Pan; Zhang, Shusen; Li, Manhua; Ding, Haifang; Yang, Lei

doi:10.1007/s13277-015-3839-7

Cited by 24 publications

(17 citation statements)

References 30 publications

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“…CRM1, for example, has been identified as a suitable marker for poor prognosis in gastric, ovarian, pancreatic and brain cancer as well as in acute myeloid leukemia and osteosarcoma [ 35 , 36 , 37 , 38 , 39 , 40 ]. Moreover, importin β1 has been identified as marker for poor prognosis in gastric cancer [ 41 ], while the nuclear expression of the export receptor CAS associates with lower overall survival and highly aggressive tumors in bladder and ovarian cancer, respectively [ 42 , 43 ].…”

Section: Pathophysiological Relevance Of Nucleocytoplasmic Transpomentioning

confidence: 99%

Controlling the Gatekeeper: Therapeutic Targeting of Nuclear Transport

Kosyna

Depping

2018

Cells

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Nuclear transport receptors of the karyopherin superfamily of proteins transport macromolecules from one compartment to the other and are critical for both cell physiology and pathophysiology. The nuclear transport machinery is tightly regulated and essential to a number of key cellular processes since the spatiotemporally expression of many proteins and the nuclear transporters themselves is crucial for cellular activities. Dysregulation of the nuclear transport machinery results in localization shifts of specific cargo proteins and associates with the pathogenesis of disease states such as cancer, inflammation, viral illness and neurodegenerative diseases. Therefore, inhibition of the nuclear transport system has future potential for therapeutic intervention and could contribute to the elucidation of disease mechanisms. In this review, we recapitulate clue findings in the pathophysiological significance of nuclear transport processes and describe the development of nuclear transport inhibitors. Finally, clinical implications and results of the first clinical trials are discussed for the most promising nuclear transport inhibitors.

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Section: Pathophysiological Relevance Of Nucleocytoplasmic Transpomentioning

confidence: 99%

Controlling the Gatekeeper: Therapeutic Targeting of Nuclear Transport

Kosyna

Depping

2018

Cells

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“…Thus, the identification of genes and pathways involved in and/or altered in this process will not only improve our understanding of cancer initiation and development, but will also help in the identification of novel anticancer drug targets. Previous studies have revealed Karyopherin β1 (Kpnβ1), the primary nuclear import protein, to be significantly overexpressed in a variety of cancer types including cervical [ 10 ], gastric [ 30 ], and breast cancers [ 13 ]. Furthermore, these studies reveal that inhibition of Kpnβ1 expression leads to cancer cell death, while inhibition in non-cancer cells has only a minor effect on cell viability [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

A tight balance of Karyopherin β1 expression is required in cervical cancer cells

et al. 2018

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BackgroundKaryopherin β1 (Kpnβ1) is the main nuclear import protein involved in the transport of cargoes from the cytoplasm into the cell nucleus. Previous research has found Kpnβ1 to be significantly overexpressed in cervical cancer and other cancer tissues, and further studies showed that inhibition of Kpnβ1 expression by siRNA resulted in cancer cell death, while non-cancer cells were minimally affected. These results suggest that Kpnβ1 has potential as an anticancer therapeutic target, thus warranting further research into the association between Kpnβ1 expression and cancer progression. Here, the biological effects associated with Kpnβ1 overexpression were investigated in order to further elucidate the relationship between Kpnβ1 and the cancer phenotype.MethodsTo evaluate the effect of Kpnβ1 overexpression on cell biology, cell proliferation, cell cycle, cell morphology and cell adhesion assays were performed. To determine whether Kpnβ1 overexpression influences cell sensitivity to chemotherapeutic agents like Cisplatin, cell viability assays were performed. Expression levels of key proteins were analysed by Western blot analysis.ResultsOur data revealed that Kpnβ1 overexpression, above that which was already detected in cancer cells, resulted in reduced proliferation of cervical cancer cells. Likewise, normal epithelial cells showed reduced proliferation after Kpnβ1 overxpression. Reduced cancer cell proliferation was associated with a delay in cell cycle progression, as well as changes in the morphology and adhesion properties of cells. Additionally, Kpnβ1 overexpressing HeLa cells exhibited increased sensitivity to cisplatin, as shown by decreased cell viability and increased apoptosis, where p53 and p21 inhibition reduced and enhanced cell sensitivity to Cisplatin, respectively.ConclusionsOverall, our results suggest that a tight balance of Kpnβ1 expression is required for cellular function, and that perturbation of this balance results in negative effects associated with a variety of biological processes.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5044-8) contains supplementary material, which is available to authorized users.

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“…Recently, it has been shown that Impβ expression is increased in several malignant tumors such as cervical tumors and malignant peripheral nerve sheath tumors (MPNSTs) as well as in breast, gastritic, neck, lung and ovarian cancers [ 145 , 158 , 159 , 160 , 161 , 162 ]. Impβ up-regulation has been shown to promote cell proliferation in gastritic and cervical cancer cells [ 145 , 158 ]. Also, one of the adaptor molecules Karyopherin α2 bridging the interaction between Impβ and NLS-bearing cargo is a potential biomarker in multiple cancers reviewed in [ 163 ].…”

Section: The Nucleocytoplasmic Transport Machinerymentioning

confidence: 99%

Structural Basis of Targeting the Exportin CRM1 in Cancer

Dickmanns

Monecke

Ficner

2015

Cells

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Recent studies have demonstrated the interference of nucleocytoplasmic trafficking with the establishment and maintenance of various cancers. Nucleocytoplasmic transport is highly regulated and coordinated, involving different nuclear transport factors or receptors, importins and exportins, that mediate cargo transport from the cytoplasm into the nucleus or the other way round, respectively. The exportin CRM1 (Chromosome region maintenance 1) exports a plethora of different protein cargoes and ribonucleoprotein complexes. Structural and biochemical analyses have enabled the deduction of individual steps of the CRM1 transport cycle. In addition, CRM1 turned out to be a valid target for anticancer drugs as it exports numerous proto-oncoproteins and tumor suppressors. Clearly, detailed understanding of the flexibility, regulatory features and cooperative binding properties of CRM1 for Ran and cargo is a prerequisite for the design of highly effective drugs. The first compound found to inhibit CRM1-dependent nuclear export was the natural drug Leptomycin B (LMB), which blocks export by competitively interacting with a highly conserved cleft on CRM1 required for nuclear export signal recognition. Clinical studies revealed serious side effects of LMB, leading to a search for alternative natural and synthetic drugs and hence a multitude of novel therapeutics. The present review examines recent progress in understanding the binding mode of natural and synthetic compounds and their inhibitory effects.

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Upregulation of KPNβ1 in gastric cancer cell promotes tumor cell proliferation and predicts poor prognosis

Cited by 24 publications

References 30 publications

Controlling the Gatekeeper: Therapeutic Targeting of Nuclear Transport

Controlling the Gatekeeper: Therapeutic Targeting of Nuclear Transport

A tight balance of Karyopherin β1 expression is required in cervical cancer cells

Structural Basis of Targeting the Exportin CRM1 in Cancer

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