p53-independent p21 induction by MELK inhibition

Matsuda, Tatsuo; Kato, Taigo; Kiyotani, Kazuma; Tarhan, Yunus Emre; Saloura, Vassiliki; Chung, Suyoun; Ueda, Koji; Park, Jae-Hyun

doi:10.18632/oncotarget.18488

Cited by 41 publications

(33 citation statements)

References 23 publications

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“…In addition, in accordance with bioinformatics analyses of GSE13507, MELK was involved in the cell cycle, G1/S transition of the mitotic cell cycle, DNA repair and replication, which was similar to previous reports 6,26,33,[39][40][41][42][43]. A, The expression of MELK was up-regulated at transcription level with MELK plasmid; it was down-regulated by OTSSP167.…”

supporting

confidence: 90%

Inhibition of MELK produces potential anti‐tumour effects in bladder cancer by inducing G1/S cell cycle arrest via the ATM/CHK2/p53 pathway

Chen

Zhou

Guo

et al. 2019

J Cellular Molecular Medi

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We aimed to investigate the biological function of MELK and the therapeutic potential of OTSSP167 in human bladder cancer (BCa). First, we observed overexpression of MELK in BCa cell lines and tissues and found that it was associated with higher tumour stage and tumour grade, which was consistent with transcriptome analysis.High expression of MELK was significantly correlated with poor prognosis in BCa patients, and MELK was found to have a role in the cell cycle, the G1/S transition in mitosis, and DNA repair and replication. Furthermore, BCa cells presented significantly decreased proliferation capacity following silencing of MELK or treatment with OTSSP167 in vitro and in vivo. Functionally, reduction in MELK or treatment of cells with OTSSP167 could induce cell cycle arrest and could suppress migration. In addition, these treatments could activate phosphorylation of ATM and CHK2, which would be accompanied by down-regulated MDMX, cyclin D1, CDK2 and E2F1; however, p53 and p21 would be activated. Opposite results were observed when MELK expression was induced. Overall, MELK was found to be a novel oncogene in BCa that induces cell cycle arrest via the ATM/CHK2/p53 pathway. OTSSP167 displays potent anti-tumour activities, which may provide a new molecule-based strategy for BCa treatment. K E Y W O R D S bladder cancer, cell cycle, MELK, OTSSP167, p53 | 1805 CHEN Et al.

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supporting

confidence: 90%

Inhibition of MELK produces potential anti‐tumour effects in bladder cancer by inducing G1/S cell cycle arrest via the ATM/CHK2/p53 pathway

Chen

Zhou

Guo

et al. 2019

J Cellular Molecular Medi

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“…Another two studies reported that MELK expression is associated with tumor cell mitosis and promotes tumor cell proliferation . MELK also plays an important role in the P53‐P21 apoptotic pathway . Based on the above findings, we used different concentrations of inhibitor OTSSP167 and siRNA knockdown MELK to detect cervical cell proliferation, colony formation ability, and apoptosis‐related proteins P53, cleaved caspase‐3.…”

Section: Discussionmentioning

confidence: 93%

Maternal embryonic leucine zipper kinase: A novel biomarker and a potential therapeutic target of cervical cancer

Wang

Shen

et al. 2018

Cancer Medicine

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Maternal embryo leucine zipper kinase (MELK) is highly expressed in a variety of malignant tumors and involved in cell cycle regulation, cell proliferation, apoptosis, tumor formation etc However, the biological effects of MELK in cervical cancer are still uninvestigated. This study aimed to explore the expression of MELK in cervical cancer, as well as its effects on the proliferation, apoptosis, DNA damage repair on cervical cancer cell line in vitro and to provide novel ideas for further improving the clinical efficacy of cervical cancer. Immunohistochemistry, Western blot, RT‐qPCR, CCK8, and immunofluorescence techniques were used to detect the expression of MELK in cervical cancer tissues, paracancerous tissues, and cervical cancer cell lines. Several cervical cancer cell lines were treated with MELK knockdown by siRNA and MELK selective inhibitor OTSSP167. The effects on proliferation, apoptosis, and colony formation capacity, and tumor cell DNA damage repair‐related factor were detected in cell lines. Our data showed that the high expression rate of MELK in cervical cancer patients was 56.92%. MELK expression in cervical cancer samples was significantly higher than that in paraneoplastic tissues. Highly expressed MELK correlated with the cervical histopathological grading and greatly increased with the cervical histopathological grading, from normal cervix and cervical intraepithelial neoplasia to cervical cancer. Moreover, the abnormal expression of MELK was related to cervical cancer metastasis at early stage. The knockdown of MELK with siRNA and OTSSP167 had strong inhibition effects on the proliferation, apoptosis, and colony formation of cervical cancer cells. MELK knockdown could also aggravate the DNA damage of cervical cancer cells possibly by homologous recombination repair pathway. Therefore, MELK may be a predicting marker of poor prognosis of cervical cancer and may also be a new therapeutic target for cervical cancer, providing ideas for improving the therapeutic effect of cervical cancer.

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“…Some of the isoforms could act similar to p53 protein and play a redundant role ( Pflaum, Schlosser & Müller, 2014 ). In addition, there is plenty of other evidence to suggest that p53 pathway-related genes could be regulated in a p53-independent manner, mediated by C/EBP, Rb, Oct1/NF-Y, or MELK respectively ( Chinery et al, 1997 ; Sun et al, 1998 ; Hirose et al, 2003 ; Matsuda et al, 2017 ). It was shown previously that cellular ROS up-regulated the expression of p21 in a p53-independent manner ( Russo et al, 1995 ).…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling and functional analysis reveals that p53 pathway-related gene expression is highly activated in cancer cells treated by cold atmospheric plasma-activated medium

Shi

Feng

et al. 2017

PeerJ

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BackgroundCold atmospheric-pressure plasma (CAP) has been considered a promising strategy for anti-cancer treatment. Traditionally, CAP was employed to kill cancer cells or tumor tissues by direct irradiation. However, CAP has some disadvantages such as infiltration capacity and storage convenience. Recently, plasma-activated medium (PAM) was used as an alternative strategy to treat cancer cells or tumors. The novel PAM approach has potential as an anti-cancer therapy.ObjectiveTo reveal the global activation of signaling pathways in oral cancer cells induced by PAM.MethodsOral squamous cell line SCC15 were treated by PAM and gene expression profiles were evaluated by using RNA-seq. Functional analyses were employed to reveal the global responses of SCC15 cells with PAM stimulation. QRT-PCR and Western blot were carried out to validate the expression levels of selected genes.ResultsMore than 6G clean data per sample were obtained in PAM-treated SCC15 cells. A total of 934 differentially expressed genes (DEGs) were identified and GO analysis implicated the deep involvement of biological process. KEGG mapping further clustered 40 pathways, revealing that “p53 pathway” was significantly enriched. SCC15 cells were commonly used as a p53-null cell line. Therefore, the enriched p53 pathway-related genes in our analysis might be activated by other stimulators, in a p53-independent manner. Gene set enrichment analysis (GSEA) was also performed to evaluate changes at the gene-sets level. The results demonstrated not only the high engagement of “p53 pathway” but also the involvement of novel pathways such as hypoxia pathway.ConclusionsThe present study elucidates the transcriptomic changes of PAM treated SCC15 cells, containing highly enriched DEGs involved in “p53 pathway”. Our analysis in this work not only provides genomic resources for future studies but also gives novel insights to uncover the molecular mechanism of PAM stimulation.

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p53-independent p21 induction by MELK inhibition

Cited by 41 publications

References 23 publications

Inhibition of MELK produces potential anti‐tumour effects in bladder cancer by inducing G1/S cell cycle arrest via the ATM/CHK2/p53 pathway

Inhibition of MELK produces potential anti‐tumour effects in bladder cancer by inducing G1/S cell cycle arrest via the ATM/CHK2/p53 pathway

Maternal embryonic leucine zipper kinase: A novel biomarker and a potential therapeutic target of cervical cancer

Gene expression profiling and functional analysis reveals that p53 pathway-related gene expression is highly activated in cancer cells treated by cold atmospheric plasma-activated medium

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