Restoration of contact inhibition in human glioblastoma cell lines after MIF knockdown

Abstract

BackgroundStudies of the role of the cytokine macrophage-migration-inhibitory-factor (MIF) in malignant tumors have revealed its stimulating influence on cell-cycle progression, angiogenesis and anti-apoptosis.ResultsHere we show that in vitro targeting MIF in cultures of human malignant glioblastoma cells by either antisense plasmid introduction or anti-MIF antibody treatment reduced the growth rates of tumor cells. Of note is the marked decrease of proliferation under confluent and over-confluent conditions, implying a role of MIF in overcoming contact inhibition. Several proteins involved in contact inhibition including p27, p21, p53 and CEBPalpha are upregulated in the MIF antisense clones indicating a restoration of contact inhibition in the tumor cells. Correspondingly, we observed a marked increase in MIF mRNA and protein content under higher cell densities in LN18 cells. Furthermore, we showed the relevance of the enzymatic active site of MIF for the proliferation of glioblastoma cells by using the MIF-tautomerase inhibitor ISO-1.ConclusionOur study adds another puzzle stone to the role of MIF in tumor growth and progression by showing the importance of MIF for overcoming contact inhibition.

Macrophage Migration Inhibitory Factor and Stearoyl-CoA Desaturase 1: Potential Prognostic Markers for Soft Tissue Sarcomas Based on Bioinformatics Analyses

“…(S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), which has been used for the treatment of various inflammatory diseases, was reported to be an inhibitor of the biological activity of MIF [42]. Subsequent to our report[12], in vitro MIF inhibition experiments have been conducted using small molecules for various cancers, such as colon cancer inhibited by ISO-1 [43], prostate cancer inhibited by ISO-1 [44], lung cancer inhibited by ISO-1 [45], and 4-Iodo-6-phenylpyrimidine (4-IPP) [45], glioblastoma inhibited by ISO-1[46-48], and adenoid cystic carcinoma inhibited by ISO-1[49]. In addition, several experiments have been conducted on animal models ( in vivo ) such as those for colorectal cancer inhibited by ISO-1 [50], and prostate cancer inhibited by ISO-1 [44].…”

“…However, the cancer cell growth assay is not the first report of the use of MIF or SCD1 inhibitors to retard cancer cell growth. MIF or SCD1 inhibitors have been used to restrict the growth or metastasis of many types of cancers [43-48,56-60], although not STS. Moreover, gene silencing of MIF or SCD1 has been carried out for many kinds of cancers [44,48,54,59-67], again with the exception of STS.…”

“…MIF or SCD1 inhibitors have been used to restrict the growth or metastasis of many types of cancers [43-48,56-60], although not STS. Moreover, gene silencing of MIF or SCD1 has been carried out for many kinds of cancers [44,48,54,59-67], again with the exception of STS. Although MIF- or SCD1 inhibition has not been reported in the case of STS, and our assay is insufficient to show the effects of MIF- or SCD1-inhibition for STS, many previous studies have suggested that MIF and SCD1 are potential therapeutic targets in the treatment of STS patients.…”

Role of macrophage migration inhibitory factor in head and neck cancer and novel therapeutic targets: A systematic review

“…Our review of the literature identified 3 main pathways that may be targets of therapy (see Figure ). First, some inhibitors of MIF (S,R‐3‐(4‐hydroxyphenyl)‐4,5‐dihydro‐5‐isoxazole acetic acid methyl ester and 4‐IPP) have already shown a therapeutic effect on cell proliferation in many cancers (ie, HNSCC, glioma, and colorectal adenocarcinoma) . Other studies conducted on leukemia, lymphoma, and prostate and ovarian cancers have also shown the possible clinical benefits of such therapeutic strategies.…”

Estudo do Fator Inibitório da Migração de Macrófagos(MIF) em pacientes com carcinoma epidermoide da cavidade bucal

“…Hypoxia-Inducible Factor 1-alpha HAGEMANN, 2013;DOUGLAS et al, 2004;DUFFY et al, 2008;FELLER;ALTINI;LEMMER, 2013;HAMATAKE et al, 2008;HATHAWAY et al, 2005;MANTOVANI;GARLANDA;ALLAVENA, 2010;MURAMAKI et al, 2006;TAKES et al, 2008) O FANG et al, 2008;KAMIMURA et al, 2000;MOHRI et al, 2009;REN et al, 2005;TOMIYASU et al , 2002;XIA et al, 2005;YASASEVER et al, 2007) DENZ et al, 2010;KROCKENBERGER et al, 2010;LEE et al, 2008;LI et al, 2009;MCCLELLAND et al, 2009;RENDON et al, 2009;SCHRADER et al, 2009;SUN et al, 2005;VERJANS et al, 2009, WU et al, 2009 Alguns dos mecanismos pelos quais a MIF induz o desenvolvimento tumoral estão associados às vias Phosphoinositide 3-Kinase/protein kinase B (PI3K/AKT), Retinoblastoma/Early-region-2 transcription factor (Rb/E2F),…”