CRM1 inhibitor S109 suppresses cell proliferation and induces cell cycle arrest in renal cancer cells

Liu, Xuejiao; Chong, Yulong; Liu, Huize; Han, Yan; Niu, Mingshan

doi:10.4196/kjpp.2016.20.2.161

Cited by 9 publications

(13 citation statements)

References 34 publications

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“…Although this gene has been detected in both kidney tumors and non-tumorous kidney tissues, its expression in patients with metastatic disease was higher than that in those without metastasis. RAN binding protein 1 gene (Ranbp1) encodes a protein that forms a complex with Ras-related nuclear protein (Ran) and metabolizes guanoside triphosphate (GTP), this complex participates in cell cycle regulation by controlling the transport of proteins and nucleic acids into the nucleus (Liu et al, 2016). Cell growth and cell cycle regulation are important events in carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the early-response genes in chemical-induced renal carcinogenicity for the prediction of chemical carcinogenicity in rats

2017

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-This study was designed to identify early-response genes of chemical-induced renal carcinogenicity for the prediction of chemical carcinogenicity in rats. We conducted a 28-day repeated-dose test in male Crl:CD (SD) rats with 12 carcinogens and 10 non-carcinogens as the training dataset, and five carcinogens and five non-carcinogens as the validation dataset. Renal gene expression profiles were analyzed by using a microarray. Fifteen candidate genes were selected from the gene expression profiles of the training dataset as genes that showed specific expression in response to carcinogens. To assess the prediction performance of the candidate genes for renal carcinogenicity, a prediction formula was developed on the basis of the gene expression data. When this formula was applied to the training dataset to check its predictive performance, all of the carcinogens and non-carcinogens were predicted correctly; the prediction formula was then applied to the validation dataset, and five carcinogens and four non-carcinogens were correctly predicted. However, 4-Hydroxy-m-phenylenediammonium dichloride (AMIDOL), a known non-renal carcinogen, was judged as positive. Therefore, the accuracy of the prediction formula for renal carcinogenicity was 100% for the training dataset and 90% for the validation dataset. Among the predictive genes, Hamp and Ranbp1 are known to be important for cell growth and cell cycle regulation, which are important events in carcinogenesis. Given our current limited knowledge of the genes responsible for renal carcinogenesis, the identification of candidate genes of chemical-induced renal carcinogenicity by use of this gene expression-based prediction method represents a promising advance in renal carcinogen identification.

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Section: Discussionmentioning

confidence: 99%

Investigation of the early-response genes in chemical-induced renal carcinogenicity for the prediction of chemical carcinogenicity in rats

2017

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“…For the first time, a study was conducted that showed an increased expression of Crm1 in cancerous tissues, and the results of this study indicated a possible relationship between Crm1 and cancer (van der Watt et al, 2009). Additionally, it was shown in advanced studies that the increased expression of Crm1 was verified in 17 different tumor types, including multiple myeloma (Tai et al, 2014), ovarian cancer (Noske et al, 2008), osteosarcoma (Yao et al, 2009), esophageal cancer (van der Watt et al, 2014Yang et al, 2014), glioma , gastric cancer (Zhou et al, 2013), and renal cancer (Liu et al, 2016). This overexpression was correlated with poor patient survival and was reported to have a negative prognostic value (Turner et al, 2011).…”

Section: Discussionmentioning

confidence: 98%

“…It was also reported that cell cycle inhibitors involved in the pathogenesis of cancer were targeted by Crm1; tumor suppressor proteins, including BRAC1, the FOXOs, Rb, APC, RASSF2, Merlin, nucleophosmin, survivin, STAT, a κB-α inhibitor (IκB-α), and transcription factors NFY/ CBP, Sp1, and p53, are all affected by Crm1 overexpression and contribute to cellular transformations together with Crm1. Crm1 deregulation has been demonstrated mainly in cervical squamous cell carcinoma (van der Watt et al, 2009), though also in many other cancer types, such as esophageal cancer (van der Watt et al, 2014;Yang et al, 2014), multiple myeloma (Tai et al, 2014), and renal cancer (Liu et al, 2016), and it has been shown that Crm1 inhibition has the potential to target continuously proliferating cancer cells (Kau et al, 2004). Crm1-targeting agents containing inhibitors, such as LMB (Newlands et al, 1996;Wolff et al, 1997;Kudo et al, 1999), N-azolylacrylate analogs (Daelemans et al, 2002), Valeriana fauriei and Alpinia galanga l (Tamura et al, 2009), the FOXO family (Kau et al, 2003), and the novel SINE (Sakakibara et al, 2011), are highly potent candidate molecules that could be used to develop anticancer therapies when the role of Crm1 is confirmed.…”

Section: Discussionmentioning

confidence: 99%

Crm1 knockdown by specific small interfering RNA reduces cell proliferation and induces apoptosis in head and neck cancer cell lines

Özdaş¹,

Özdaş²

2018

Turk J Biol

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2014). In most cases of HNSCC, only 51% of short-term malignancies and only 10.5% of long-term malignancies could be detected even with advanced investigations. Fiveyear survival rates are 51% in short-term malignancies and 28% in long-term malignancies (Jemal et al., 2009).The underlying mechanism of HNSCC invasion and metastasis is a multistep process characterized by multiple genetic and molecular changes (Wilken et al., 2011). However, not all of the underlying molecular mechanisms of HNSCC pathology are clear. Additionally, despite the standard therapies, including radiation, surgery, and/or chemotherapy, there has been no significant change in the survival rate within the last 20-30 years, and the mortality rate for HNSCC is still high (Jemal et al., 2009). Therefore, it is very important to investigate new candidate molecules for the diagnosis, follow-up, and control of HNSCC. Moreover, the investigation of potential target molecules that may be responsible for the HNSCC pathogenesis is crucial for the development of new clinical therapeutic approaches.Chromosome region maintenance 1 (Crm1), a member of the cytoplasm-nucleus transport receptor family known as the karyopherins, is an important nuclear export protein in mammals that facilitates the transport of various classes of RNAs, proteins, and other macromolecules from the nuclear membrane to the cytoplasm, and it helps maintain their appropriate subcellular localization (Kudo et al., 1997;Nguyen et al., 2012;Turner et al., 2012). Crm1 has a broad range of substrates and recognizes numerous cargo proteins, which are rich in nuclear export signal (NES) sequences, including tumor suppressor proteins such as p53, p27, and p21. These tumor suppressor proteins carry NES sequences rich in leucine amino acids and Abstract: Head and neck squamous cell carcinoma (HNSCC) is the most common and most aggressive type of head and neck cancer. Current approaches for the treatment of HNSCC are not sufficient to increase the patient survival or to reduce the high recurrence rate. Consequently, there is a need to explore the molecular characteristics of this cancer in order to discover potential therapeutic target molecules. The overexpression of chromosome region maintenance 1 (Crm1), responsible for the transport of different classes of macromolecules from the nuclear membrane to the cytoplasm, in various cancer cells has made it an attractive target molecule in cancer research. It has been reported that transcription factors, which are the target cargo proteins of Crm1, have critical roles in regulating intracellular processes via their expression levels and functions, which in turn are regulated by the cell cycle and signaling proteins. Previous findings show that head and neck cancer cells overexpress Crm1 and that these cells become highly dependent on Crm1 function. The results of this study show that after decreasing Crm1 expression levels in HNSCC cells through either treatment with specific Crm1 RNA interference (siRNA) or the selective Crm1 inhibitor leptomyc...

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“…Liu et al found that S109 can inhibit the CRM1-mediated nuclear export of tumor suppressor protein RanBP1 and decreases the protein levels of CRM1, which indicates that CRM1 is a therapeutic target for the treatment of renal cancer and is a novel reversible CRM1 inhibitor. S109 could be a candidate for renal cancer therapy [28].…”

Section: S109mentioning

confidence: 99%

Newly-presented potential targeted drugs in the treatment of renal cell cancer

Zhang

Zheng

2016

Open Life Sciences

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Renal cell carcinoma (RCC) is the most frequent form of renal cancer, and is associated with a high frequency of metastasis. While, there is few therapeutic methods can substantially prolong survival. Superior to cytokine therapy with IL-2 and/or IFN-α, several newer targeted treatments are available for the treatment of patients with advanced conventional (clear cell) renal cell carcinoma (RCC), which received improved outcomes. These newer targeted treatments include the multi-targeted tyrosine kinase inhibitors (TKIs, sorafenib, sunitinib, pazopanib, and axitinib), the humanised antivascular endothelial growth factor (VEGF) monoclonal antibody [bevacizumab combined with interferon (IFN)-α], and mTOR (mammalian target of rapamycin) complex 1 kinase inhibitors (everolimus and temsirolimus). However, these targeted drugs are still associated with limited efficacy and high toxicity, so there is still a strong need for further discovery of new targeted drugs. In the present manuscript, we summarize newly-presented potential targeted drugs for RCC, classified by drug characteristic, small molecule, small molecule combination, monoclonal antibody, polysaccharides, organometals and peptides.

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CRM1 inhibitor S109 suppresses cell proliferation and induces cell cycle arrest in renal cancer cells

Cited by 9 publications

References 34 publications

Investigation of the early-response genes in chemical-induced renal carcinogenicity for the prediction of chemical carcinogenicity in rats

Investigation of the early-response genes in chemical-induced renal carcinogenicity for the prediction of chemical carcinogenicity in rats

Crm1 knockdown by specific small interfering RNA reduces cell proliferation and induces apoptosis in head and neck cancer cell lines

Newly-presented potential targeted drugs in the treatment of renal cell cancer

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