title: mTOR inhibitor temsirolimus and MEK1/2 inhibitor U0126 promote chromosomal instability and cell type-dependent phenotype changes of glioblastoma cells.
abstract: The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and the RAF/mitogen-activated and extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways are frequently deregulated in cancer. Temsirolimus (TEM) and its primary active metabolite rapamycin allosterically block mTOR complex 1 substrate recruitment. The context-/experimental setup-dependent opposite effects of rapamycin on the multiple centrosome formation, aneuploidy, DNA damage/repair, proliferation, and invasion were reported. Similarly, the context-dependent either tumor-promoting or suppressing effects of RAF-MEK-ERK pathway and its inhibitors were demonstrated. Drug treatment-mediated stress may promote chromosomal instability (CIN), accelerating changes in the genomic landscape and phenotype diversity. Here, we characterized the genomic and phenotypic changes of U251 and T98G glioblastoma cell lines long-term treated with TEM or U0126, an inhibitor of MEK1/2. TEM significantly increased clonal and non-clonal chromosome aberrations. Both TEM and U0126 affected copy number alterations (CNAs) pattern. A proliferation rate of U251TEM and U251U0126 cells was lower and higher, respectively, than control cells. Colony formation efficiency of U251TEM significantly decreased, whereas U251U0126 did not change. U251TEM and U251U0126 cells decreased migration. In contrast, T98GTEM and T98GU0126 cells did not change proliferation, colony formation efficiency, and migration. Changes in the sensitivity of inhibitor-treated cells to the reduction of the glucose concentration were observed. Our results suggest that CIN and adaptive reprogramming of signal transduction pathways may be responsible for the cell type-dependent phenotype changes of long-term TEM- or U0126-treated tumor cells.
authors.affiliation: Department of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics, Zabolotnogo Str. 150, Kyiv 03680, Ukraine. Electronic address: a.a.stepanenko@gmail.com.
authors.forename: A A
authors.initials: AA
authors.lastname: Stepanenko
authors.affiliation: Department of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics, Zabolotnogo Str. 150, Kyiv 03680, Ukraine.
authors.forename: S V
authors.initials: SV
authors.lastname: Andreieva
authors.affiliation: Department of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics, Zabolotnogo Str. 150, Kyiv 03680, Ukraine.
authors.forename: K V
authors.initials: KV
authors.lastname: Korets
authors.affiliation: Department of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics, Zabolotnogo Str. 150, Kyiv 03680, Ukraine.
authors.forename: D O
authors.initials: DO
authors.lastname: Mykytenko
authors.affiliation: Department of Medicinal Nanobiotechnology, Pirogov Russian State Medical University, Ostrovitianov str. 1, Moscow 117997, Russia; Federal Research and Clinical Centre, FMBA of Russia, Orekhoviy bulvar str. 28, Moscow 115682, Russia.
authors.forename: V P
authors.initials: VP
authors.lastname: Baklaushev
authors.affiliation: Department of Medicinal Nanobiotechnology, Pirogov Russian State Medical University, Ostrovitianov str. 1, Moscow 117997, Russia.
authors.forename: V P
authors.initials: VP
authors.lastname: Chekhonin
authors.affiliation: Department of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics, Zabolotnogo Str. 150, Kyiv 03680, Ukraine.
authors.forename: V V
authors.initials: VV
authors.lastname: Dmitrenko
mesh_terms: D002070:Butadienes / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D043171:Chromosomal Instability; D005909:Glioblastoma / Q000235:genetics*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology*; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D002070:Butadienes; D009570:Nitriles; D047428:Protein Kinase Inhibitors; C113580:U 0126; C401859:temsirolimus; D005947:Glucose; D020123:Sirolimus
keywords: Aneuploidy; BRAF; Chromosomal instability; Drug resistance; ERK1/2; Everolimus; Glioblastoma; Glioma; Karyotype; MEK1/2; Rapamycin; Targeted therapy; Temsirolimus; Tumor evolution; Tumor heterogeneity; U0126; mTOR complex