Relevant coexpression of STMN1, MELK and FOXM1 in glioblastoma and review of the
            impact of STMN1 in cancer biology

Serachi, Fernanda de Oliveira; Marie, Suely Kazue Nagahashi; Oba-Shinjo, Sueli Mieko

doi:10.5935/medicalexpress.2017.05.06

Cited by 5 publications

(4 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It is also an important carcinogen for the pathogenesis of GBM ( 17 ). MELK expression is negatively correlated with GBM survival rate ( 18 ). MELK regulates GBM malignant proliferation and progression ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

MELK Inhibition Effectively Suppresses Growth of Glioblastoma and Cancer Stem-Like Cells by Blocking AKT and FOXM1 Pathways

Zhang

Wang

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) is a devastating disease yet no effective drug treatment has been established to date. Glioblastoma stem-like cells (GSCs) are insensitive to treatment and may be one of the reasons for the relapse of GBM. Maternal embryonic leucine zipper kinase gene (MELK) plays an important role in the malignant proliferation and the maintenance of GSC stemness properties of GBM. However, the therapeutic effect of targeted inhibition of MELK on GBM remains unclear. This study analyzed the effect of a MELK oral inhibitor, OTSSP167, on GBM proliferation and the maintenance of GSC stemness. OTSSP167 significantly inhibited cell proliferation, colony formation, invasion, and migration of GBM. OTSSP167 treatment reduced the expression of cell cycle G2/M phase-related proteins, Cyclin B1 and Cdc2, while up-regulation the expression of p21 and subsequently induced cell cycle arrest at the G2/M phase. OTSSP167 effectively prolonged the survival of tumor-bearing mice and inhibited tumor cell growth in in vivo mouse models. It also reduced protein kinase B (AKT) phosphorylation levels by OTSSP167 treatment, thereby disrupting the proliferation and invasion of GBM cells. Furthermore, OTSSP167 inhibited the proliferation, neurosphere formation and self-renewal capacity of GSCs by reducing forkhead box M1 (FOXM1) phosphorylation and transcriptional activity. Interestingly, the inhibitory effect of OTSSP167 on the proliferation of GSCs was 4-fold more effective than GBM cells. In conclusion, MELK inhibition suppresses the growth of GBM and GSCs by double-blocking AKT and FOXM1 signals. Targeted inhibition of MELK may thus be potentially used as a novel treatment for GBM.

show abstract

Section: Introductionmentioning

confidence: 99%

“…MELK expression is negatively correlated with GBM survival rate ( 18 ). MELK regulates GBM malignant proliferation and progression ( 18 ). In addition, high MELK expression is closely related to the maintenance of stemness properties of GSCs.…”

Section: Introductionmentioning

confidence: 99%

MELK Inhibition Effectively Suppresses Growth of Glioblastoma and Cancer Stem-Like Cells by Blocking AKT and FOXM1 Pathways

Zhang

Wang

et al. 2021

Front. Oncol.

View full text Add to dashboard Cite

show abstract

“…Accordingly, disturbances to the cell cycle with subsequent appearance of subG1 apoptotic peaks in TCEP-exposed cells legibly justifies the upregulation of STMN1 . On top of that, STMN1 is phosphorylated by MAPKs during intracellular signaling [ 50 ]. In this relation, upregulation of MAP2K14 in HepG2 cells signifies its divergent role to regulate STMN1 expression.…”

Section: Discussionmentioning

confidence: 99%

Tris(2-chloroethyl) Phosphate (TCEP) Elicits Hepatotoxicity by Activating Human Cancer Pathway Genes in HepG2 Cells

Alsalem

Saquib

Siddiqui

et al. 2020

Toxics

View full text Add to dashboard Cite

Tris(2-chloroethyl) phosphate (TCEP) is one of the organophosphorus flame retardants (OPFRs) used in consumer commodities and have been detected in human body fluids. Research on TCEP-induced transcriptomic alterations and toxicological consequences in liver cells is still lacking. Herein, human hepatocellular (HepG2) cells were treated with 100, 200, and 400 μM TCEP for 3 days to quantify hepatotoxicity by MTT, NRU, and comet assays. Apoptosis, mitochondrial membrane potential (ΔΨm), oxidative stress, and Ca2+ influx were measured by flow cytometry. A qPCR array was employed for transcriptomic analysis. MTT and NRU data showed 70.92% and 75.57% reduction in cell survival at 400 μM. In addition, 20-fold greater DNA damage was recorded at 400 μM. Cell cycle data showed 65.96% subG1 apoptotic peak in 400 μM treated cells. An elevated level of oxidative stress, esterase, Ca2+ influx, and ΔΨm dysfunction were recorded in TCEP-treated cells. Out of 84 genes, the qPCR array showed upregulation of 17 genes and downregulation of 10 key genes belonging to human cancer pathways. Our study endorses the fact that TCEP possesses hepatotoxic potential at higher concentrations and prolonged exposure. Hence, TCEP may act as a cancer-inducing entity by provoking the gene network of human cancer pathways.

show abstract

“…A desfosforilação STMN1 ativa a proteína, causando no sequestro de tubulina. Esta dinâmica de ativação / inativação de STMN1 resulta em despolimerização / polimerização de microtúbulos e, consequentemente, da progressão do ciclo celular / proliferação, transição epitéliomesênquima e quimiorresistência (Serachi et al, 2017).…”

Section: Análise Do Efeito Do Silenciamento De Stmn1 Na Proliferaçãounclassified

O papel de STMN1 e MELK em astrocitoma humano

Serachi¹

Self Cite

View full text Add to dashboard Cite

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and standard treatment consists of surgical resection of the tumor, followed by radiation and chemotherapy with temozolomide. Our group performed the analysis of differently expressed genes between GBM and pilocytic astrocytoma. One of the genes with increased expression in GBMs was MELK (maternal embryonic leucine zipper kinase), which encodes a serine / threonine kinase protein that plays an important role in various cellular processes, such as proliferation, cell cycle, apoptosis, and oncogenesis. A siRNA silenced GBM cell analysis was performed to identify possible genes associated with the MELK pathway. One of the genes identified was STMN1, which encodes stathmin 1, an important cytosolic protein that plays a critical role in mitosis by regulating microtubule dynamics during cell cycle progression and migration. In addition, STMN1 is also involved in other biological processes, such as migrating and differentiating, through the phosphorylation of four serines (S16, S25, S38 and S63) triggers protein activation, weakening its binding to tubulin molecules. FOXM1, an important transcription factor, identified as regulator in the expression of several genes essential for cell cycle progression, including STMN1, was also a target of this study. In addition, FOXM1 is phosphorylated by MELK, regulating mitosis. MELK, STMN1 and FOXM1 are still related to tumor cell resistance to chemotherapy treatment. The aim of this study was to analysize expression levels of MELK, STMN1 and FOXM1 in our cohort astrocytomas of different degrees of malignancy. In addition, these data were validated in silico in larger cohorts of The Cancer Genome Atlas (TCGA). The expression of the three genes increased according to the malignancy of astrocytomas in our cases and in TCGA cases. MELK and STMN1, MELK and FOXM1 and STMN1 and FOXM1 expression levels were positively correlated in our GBM series, as well as in the TCGA series. In addition, the three genes showed higher expression in the proneural GBM subtype than in the Mesenquimal and Clássico subtypes in the case series of TCGA. U87MG and A172 cells silenced with MELK siRNA showed a similar decrease in MELK and STMN1 expression (~90%), but with a lower level of FOXM1 decrease (~50%). Phosphorylated serines of STMN1 were also analyzed after MELK silencing, and there was a decrease in phosphorylation compared to the control. On the other hand, when STMN1 expression was silenced with siRNA, MELK expression did not change and FOXM1 expression decreased by 40%. Silenced cells showed a reduction in cell viability and migration. Additionally, GBM cases were divided based on the expression of high and low STMN1. Of the cases with increased STMN1 expression, 79% showed increased FOXM1 expression, compared to 25% in the low STMN1 expression group. However, these groups showed no difference in survival of patients. The relationship between the three genes and drug resistance was analyzed in temozolamide and vinc...

show abstract

Relevant coexpression of STMN1, MELK and FOXM1 in glioblastoma and review of the impact of STMN1 in cancer biology

Cited by 5 publications

References 68 publications

MELK Inhibition Effectively Suppresses Growth of Glioblastoma and Cancer Stem-Like Cells by Blocking AKT and FOXM1 Pathways

MELK Inhibition Effectively Suppresses Growth of Glioblastoma and Cancer Stem-Like Cells by Blocking AKT and FOXM1 Pathways

Tris(2-chloroethyl) Phosphate (TCEP) Elicits Hepatotoxicity by Activating Human Cancer Pathway Genes in HepG2 Cells

O papel de STMN1 e MELK em astrocitoma humano

Contact Info

Product

Resources

About