Dataset Information

High expression of maternal embryonic leucine-zipper kinase (MELK) impacts clinical outcomes in patients with ovarian cancer and its inhibition suppresses ovarian cancer cells growth ex vivo.

ABSTRACT: OBJECTIVE:Maternal embryonic leucine zipper kinase (MELK) is receiving an attention as a therapeutic target in various types of cancers. In this study, we aimed to evaluate the prognostic significance of MELK expression in ovarian cancer using clinical samples, and assessed the efficacy of a small molecule MELK inhibitor, OTS167, using patient-derived ovarian cancer cells as well as cell lines. METHODS:Expression levels of MELK in 11 ovarian cancer cell lines were confirmed by western blotting. Inhibitory concentration of OTS167 was determined by colorimetric assay. MELK messenger RNA (mRNA) expression was evaluated in 228 ovarian cancer patients by quantitative polymerase chain reaction. Growth inhibition of OTS167 was also evaluated using freshly-isolated primary ovarian cancer cells including spheroid formation condition. RESULTS:MELK mRNA expression was significantly higher in ovarian cancer than in normal ovaries (p<0.001), and high MELK mRNA expression was observed in patients with advanced stage, positive ascites cytology and residual tumor size. Patients with high MELK mRNA expression showed shorter progression-free survival (p=0.001). Expression of MELK was also confirmed in 10 of 11 ovarian cancer cell lines tested, and the half maximal inhibitory concentration of MELK inhibitor, OTS167, ranged from 9.3 to 60 nM. Additionally, OTS167 showed significant growth inhibitory effect against patient-derived ovarian cancer cells, regardless of their tumor locations, histologic subtypes and stages. CONCLUSIONS:We demonstrated MELK as both a prognostic marker and a therapeutic target for ovarian cancer using clinical ovarian cancer samples. MELK inhibition by OTS167 may be an effective approach to treat ovarian cancer patients.

SUBMITTER: Ikeda Y

PROVIDER: S-EPMC7593222 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

High expression of maternal embryonic leucine-zipper kinase (MELK) impacts clinical outcomes in patients with ovarian cancer and its inhibition suppresses ovarian cancer cells growth ex vivo.

Ikeda Yuji Y Sato Sho S Yabuno Akira A Shintani Daisuke D Ogasawara Aiko A Miwa Maiko M Zewde Makda M Miyamoto Takashi T Fujiwara Keiichi K Nakamura Yusuke Y Hasegawa Kosei K

Journal of gynecologic oncology 20201101 6

<h4>Objective</h4>Maternal embryonic leucine zipper kinase (MELK) is receiving an attention as a therapeutic target in various types of cancers. In this study, we aimed to evaluate the prognostic significance of <i>MELK</i> expression in ovarian cancer using clinical samples, and assessed the efficacy of a small molecule MELK inhibitor, OTS167, using patient-derived ovarian cancer cells as well as cell lines.<h4>Methods</h4>Expression levels of MELK in 11 ovarian cancer cell lines were confirmed ...[more]

PMID: 33078598

Similar Datasets

Project description:IntroductionCancer therapies directed at specific molecular targets in signaling pathways of cancer cells, such as tamoxifen, aromatase inhibitors and trastuzumab, have proven useful for treatment of advanced breast cancers. However, increased risk of endometrial cancer with long-term tamoxifen administration and of bone fracture due to osteoporosis in postmenopausal women undergoing aromatase inhibitor therapy are recognized side effects. These side effects as well as drug resistance make it necessary to search for novel molecular targets for drugs on the basis of well-characterized mechanisms of action.MethodsUsing accurate genome-wide expression profiles of breast cancers, we found maternal embryonic leucine-zipper kinase (MELK) to be significantly overexpressed in the great majority of breast cancer cells. To assess whether MELK has a role in mammary carcinogenesis, we knocked down the expression of endogenous MELK in breast cancer cell lines using mammalian vector-based RNA interference. Furthermore, we identified a long isoform of Bcl-G (Bcl-GL), a pro-apoptotic member of the Bcl-2 family, as a possible substrate for MELK by pull-down assay with recombinant wild-type and kinase-dead MELK. Finally, we performed TUNEL assays and FACS analysis, measuring proportions of apoptotic cells, to investigate whether MELK is involved in the apoptosis cascade through the Bcl-GL-related pathway.ResultsNorthern blot analyses on multiple human tissues and cancer cell lines demonstrated that MELK was overexpressed at a significantly high level in a great majority of breast cancers and cell lines, but was not expressed in normal vital organs (heart, liver, lung and kidney). Suppression of MELK expression by small interfering RNA significantly inhibited growth of human breast cancer cells. We also found that MELK physically interacted with Bcl-GL through its amino-terminal region. Immunocomplex kinase assay showed that Bcl-GL was specifically phosphorylated by MELK in vitro. TUNEL assays and FACS analysis revealed that overexpression of wild-type MELK suppressed Bcl-GL-induced apoptosis, while that of D150A-MELK did not.ConclusionOur findings suggest that the kinase activity of MELK is likely to affect mammary carcinogenesis through inhibition of the pro-apoptotic function of Bcl-GL. The kinase activity of MELK could be a promising molecular target for development of therapy for patients with breast cancers.

Dataset Information

High expression of maternal embryonic leucine-zipper kinase (MELK) impacts clinical outcomes in patients with ovarian cancer and its inhibition suppresses ovarian cancer cells growth ex vivo.

Publications

High expression of maternal embryonic leucine-zipper kinase (MELK) impacts clinical outcomes in patients with ovarian cancer and its inhibition suppresses ovarian cancer cells growth ex vivo.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets