MELK expression in ovarian cancer correlates with poor outcome and its inhibition by OTSSP167 abrogates proliferation and viability of ovarian cancer cells

Kohler, Reto S.; Kettelhack, Henriette; Knipprath-Mészáros, Alexandra Maria; Fedier, André; Schoetzau, Andreas; Jacob, Francis; Heinzelmann‐Schwarz, Viola

doi:10.1016/j.ygyno.2017.02.016

Cited by 47 publications

(62 citation statements)

References 38 publications

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“…MELK has been reported as an important regulator of the G2/M transition in many studies. 16,[22][23][24] In contrast, MELK silencing was found to contribute to the delay of S phase progression by Beke et al and Kig et al 13,30 Our study Figure S3). Owing to the lack of additional tumour cell lines, we could not conclude that p53 affects the role of MELK in the cell cycle.…”

Section: Discussionmentioning

confidence: 59%

“…[8][9][10][11][12][13] It has been shown that MELK is overexpressed in multiple human tumours, including the following: melanoma, 8 diffuse intrinsic pontine glioma (DIPG), 14 breast cancer, 6,15 gastric cancer, 16 high-grade prostate cancer, 17 hepatocellular carcinoma, 18 kidney cancer, 19 small lung cancer, 20 myeloma, 21 acute myeloid leukaemia (AML) 22 and chronic lymphocytic leukaemia (CLL). 15,23,24 Further, genomic or pharmacologic inhibition of MELK has been shown to suppress tumour growth in vitro and in pre-clinical adult cancer models, indicating that this kinase is a potential therapeutic target. 15,23,24 Further, genomic or pharmacologic inhibition of MELK has been shown to suppress tumour growth in vitro and in pre-clinical adult cancer models, indicating that this kinase is a potential therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

“…23 High levels of MELK are correlated with clinically aggressive disease and poor survival. 19,[22][23][24][25] A number of studies have shown that MELK inhibition also increases sensitivity to radiation and chemotherapy in pre-clinical adult cancer models, suggesting that combination treatments may also be effective strategies. 19,[22][23][24][25] A number of studies have shown that MELK inhibition also increases sensitivity to radiation and chemotherapy in pre-clinical adult cancer models, suggesting that combination treatments may also be effective strategies.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…To test whether MELK inhibition would block melanoma growth, we treated melanoma cell lines with the MELK inhibitor OTSSP167 (Chung et al, 2012; Kohler et al, 2017; Wang et al, 2014). OTSSP167 treatment significantly inhibited melanoma cell line proliferation (Figure 2A) and colony formation in a soft-agar assay (Figure 2B–C and Figure S2).…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, MELK knockout mice are viable and display no adverse phenotypes (Wang et al, 2014). This information and the availability of small-molecule inhibitors of MELK with anti-cancer activity in breast and other cancers indicates that MELK might be a druggable target for cancer cell-selective therapy (Gray et al, 2005; Kohler et al, 2017; Nakano et al, 2005). …”

Section: Introductionmentioning

confidence: 99%

MELK Promotes Melanoma Growth by Stimulating the NF-κB Pathway

et al. 2017

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SUMMARY Melanoma accounts for over 80% of skin cancer-related deaths and current therapies provide only short-term benefit to patients. Here, we show in melanoma cells that maternal embryonic leucine zipper kinase (MELK) is transcriptionally upregulated by the MAP kinase pathway via transcription factor E2F1. MELK knockdown or pharmacological inhibition blocked melanoma growth and enhanced the effectiveness of BRAFV600E inhibitor against melanoma cells. To identify mediators of MELK function, we performed stable isotope labeling with amino acids in cell culture (SILAC) and identified 469 proteins that had downregulated phosphorylation after MELK inhibition. Remarkably, 139 of these proteins were previously reported as substrates of BRAF or MEK, demonstrating that MELK is an important downstream mediator of the MAPK pathway. Furthermore, we show that MELK promotes melanoma growth by activating NF-κB pathway activity via Sequestosome 1 (SQSTM1/p62). Collectively, these results underpin an important role for MELK in melanoma growth, downstream of the MAPK pathway.

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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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MELK expression in ovarian cancer correlates with poor outcome and its inhibition by OTSSP167 abrogates proliferation and viability of ovarian cancer cells

Abstract: MELK inhibition by OTSSP167 may thus present a strategy to treat patients with aggressive, progressive, and recurrent ovarian cancer.

Cited by 47 publications

References 38 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

MELK Promotes Melanoma Growth by Stimulating the NF-κB Pathway

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

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