Maternal Embryonic Leucine Zipper Kinase: Key Kinase for Stem Cell Phenotype in Glioma and Other Cancers

Ganguly, Ranjit; Hong, Christopher S.; Smith, Luke; Kornblum, Harley I.; Nakano, ﻿Ichiro

doi:10.1158/1535-7163.mct-13-0764

Cited by 61 publications

(65 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Besides being a neural stem cell marker (Glazer et al 2012), the MSI1 protein also promotes cell proliferation by suppressing p21, p27 and p53 translation (Liu et al 2014). Upregulation of MELK, encoding a serine/threonine kinase with critical role in cancer stem cell proliferation and survival (Ganguly et al 2014), was also detected in USP-13-Med cells. In brain tumor cells, both MSI1 ) and MELK (Marie et al 2008) upregulation, as well as capacity to generate tumorspheres in vitro (Panosyan et al 2010), have been correlated with poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

Establishment of a novel human medulloblastoma cell line characterized by highly aggressive stem-like cells

et al. 2015

View full text Add to dashboard Cite

Medulloblastoma is a highly aggressive brain tumor and one of the leading causes of morbidity and mortality related to childhood cancer. These tumors display differential ability to metastasize and respond to treatment, which reflects their high degree of heterogeneity at the genetic and molecular levels. Such heterogeneity of medulloblastoma brings an additional challenge to the understanding of its physiopathology and impacts the development of new therapeutic strategies. This translational effort has been the focus of most pre-clinical studies which invariably employ experimental models using human tumor cell lines. Nonetheless, compared to other cancers, relatively few cell lines of human medulloblastoma are available in central repositories, partly due to the rarity of these tumors and to the intrinsic difficulties in establishing continuous cell lines from pediatric brain tumors. Here, we report the establishment of a new human medulloblastoma cell line which, in comparison with the commonly used and well-established cell line Daoy, is characterized by enhanced proliferation and invasion capabilities, stem cell properties, increased chemoresistance, tumorigenicity in an orthotopic metastatic model, replication of original medulloblastoma behavior in vivo, strong chromosome structural instability and deregulation of genes involved in neural development. These features are advantageous for designing biologically relevant experimental models in clinically oriented studies, making this novel cell line, named USP-13-Med, instrumental for the study of medulloblastoma biology and treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Establishment of a novel human medulloblastoma cell line characterized by highly aggressive stem-like cells

et al. 2015

View full text Add to dashboard Cite

show abstract

“…MELK is a highly conserved serine/threonine kinase that was first found to be expressed in a wide range of early embryonic cellular stages, and as a result, it has been implicated in embryogenesis and cell cycle control[45]. Additionally, several studies have identified MELK overexpression in stem cell populations and several human cancers, including aggressive astrocytoma, breast cancer, prostate cancer, melanoma and GC[44-49].…”

Section: Discussionmentioning

confidence: 99%

“…Since then, novel therapeutics that selectively inhibit MELK have been developed, such as OTSSP167, which is currently in a Phase I trial for patients with solid tumors and who have not responded to treatment[45,50-53]. …”

Section: Discussionmentioning

confidence: 99%

Identification ofIL11RAandMELKamplification in gastric cancer by comprehensive genomic profiling of gastric cancer cell lines

Calcagno¹,

Takeno²,

Gigek³

et al. 2016

WJG

View full text Add to dashboard Cite

AIMTo identify common copy number alterations on gastric cancer cell lines.METHODSFour gastric cancer cell lines (ACP02, ACP03, AGP01 and PG100) underwent chromosomal comparative genome hybridization and array comparative genome hybridization. We also confirmed the results by fluorescence in situ hybridization analysis using the bacterial artificial chromosome clone and quantitative real time PCR analysis.RESULTSThe amplification of 9p13.3 was detected in all cell lines by both methodologies. An increase in the copy number of 9p13.3 was also confirmed by fluorescence in situ hybridization analysis. Moreover, the interleukin 11 receptor alpha (IL11RA) and maternal embryonic leucine zipper kinase (MELK) genes, which are present in the 9p13.3 amplicon, revealed gains of the MELK gene in all the cell lines studied. Additionally, a gain in the copy number of IL11RA and MELK was observed in 19.1% (13/68) and 55.9% (38/68) of primary gastric adenocarcinoma samples, respectively.CONCLUSIONThe characterization of a small gain region at 9p13.3 in gastric cancer cell lines and primary gastric adenocarcinoma samples has revealed MELK as a candidate target gene that is possibly related to the development of gastric cancer.

show abstract

“…It has been found to be a very potent inhibitor (IC 50 of 0.41 nM) (Chung et al, 2012) of maternal embryonic leucine zipper kinase, a protein kinase aberrantly upregulated in many types of cancer and essential for survival and proliferation of undifferentiated cancer cells (Ganguly et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Glucuronidation of OTS167 in Humans Is Catalyzed by UDP-Glucuronosyltransferases UGT1A1, UGT1A3, UGT1A8, and UGT1A10

et al. 2015

View full text Add to dashboard Cite

OTS167 is a potent maternal embryonic leucine zipper kinase inhibitor undergoing clinical testing as antineoplastic agent. We aimed to identify the UDP-glucuronosyltransferases (UGTs) involved in OTS167 metabolism, study the relationship between UGT genetic polymorphisms and hepatic OTS167 glucuronidation, and investigate the inhibitory potential of OTS167 on UGTs. Formation of a single OTS167-glucuronide (OTS167-G) was observed in pooled human liver (HLM) (K m = 3.4 6 0.2 mM), intestinal microsomes (HIM) (K m = 1.7 6 0.1 mM), and UGTs. UGT1A1 (64 ml/min/ mg) and UGT1A8 (72 ml/min/mg) exhibited the highest intrinsic clearances (CL int ) for OTS167, followed by UGT1A3 (51 ml/min/mg) and UGT1A10 (47 ml/min/mg); UGT1A9 was a minor contributor. OTS167 glucuronidation in HLM was highly correlated with thyroxine glucuronidation (r = 0.91, P < 0.0001), SN-38 glucuronidation (r = 0.79, P < 0.0001), and UGT1A1 mRNA (r = 0.72, P < 0.0001). Nilotinib (UGT1A1 inhibitor) and emodin (UGT1A8 and UGT1A10 inhibitor) exhibited the highest inhibitory effects on OTS167-G formation in HLM (68%) and HIM (47%). We hypothesize that OTS167-G is an N-glucuronide according to mass spectrometry. A significant association was found between rs6706232 and reduced OTS167-G formation (P = 0.03). No or weak UGT inhibition (range: 0-21%) was observed using clinically relevant OTS167 concentrations (0.4-2 mM). We conclude that UGT1A1 and UGT1A3 are the main UGTs responsible for hepatic formation of OTS167-G. Intestinal UGT1A1, UGT1A8, and UGT1A10 may contribute to firstpass OTS167 metabolism after oral administration.

show abstract

Maternal Embryonic Leucine Zipper Kinase: Key Kinase for Stem Cell Phenotype in Glioma and Other Cancers

Cited by 61 publications

References 45 publications

Establishment of a novel human medulloblastoma cell line characterized by highly aggressive stem-like cells

Establishment of a novel human medulloblastoma cell line characterized by highly aggressive stem-like cells

Identification ofIL11RAandMELKamplification in gastric cancer by comprehensive genomic profiling of gastric cancer cell lines

Glucuronidation of OTS167 in Humans Is Catalyzed by UDP-Glucuronosyltransferases UGT1A1, UGT1A3, UGT1A8, and UGT1A10

Contact Info

Product

Resources

About