Kinome and mRNA expression profiling of high-grade osteosarcoma cell lines implies Akt signaling as possible target for therapyReport as inadecuate




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BMC Medical Genomics

, 7:4

Functional and structural genomics

Abstract

BackgroundHigh-grade osteosarcoma is a primary malignant bone tumor mostly occurring in adolescents and young adults, with a second peak at middle age. Overall survival is approximately 60%, and has not significantly increased since the introduction of neoadjuvant chemotherapy in the 1970s. The genomic profile of high-grade osteosarcoma is complex and heterogeneous. Integration of different types of genome-wide data may be advantageous in extracting relevant information from the large number of aberrations detected in this tumor.

MethodsWe analyzed genome-wide gene expression data of osteosarcoma cell lines and integrated these data with a kinome screen. Data were analyzed in statistical language R, using LIMMA for detection of differential expression-phosphorylation. We subsequently used Ingenuity Pathways Analysis to determine deregulated pathways in both data types.

ResultsGene set enrichment indicated that pathways important in genomic stability are highly deregulated in these tumors, with many genes showing upregulation, which could be used as a prognostic marker, and with kinases phosphorylating peptides in these pathways. Akt and AMPK signaling were identified as active and inactive, respectively. As these pathways have an opposite role on mTORC1 signaling, we set out to inhibit Akt kinases with the allosteric Akt inhibitor MK-2206. This resulted in inhibition of proliferation of osteosarcoma cell lines U-2 OS and HOS, but not of 143B, which harbors a KRAS oncogenic transformation.

ConclusionsWe identified both overexpression and hyperphosphorylation in pathways playing a role in genomic stability. Kinome profiling identified active Akt signaling, which could inhibit proliferation in 2-3 osteosarcoma cell lines. Inhibition of PI3K-Akt-mTORC1 signaling may be effective in osteosarcoma, but further studies are required to determine whether this pathway is active in a substantial subgroup of this heterogeneous tumor.

KeywordsOsteosarcoma Tumor cell lines Kinome profiling Gene expression profiling Genomic instability Bone tumor AbbreviationsALLAcute lymphoblastic leukemia

DEDifferentially expressed

FDRFalse discovery rate

adjPFDR adjusted P-value

IC50Half maximal inhibitory concentration

IPAIngenuity pathways analysis

logFCLog fold change

MSCMesenchymal stem cell

Ser-ThrSerine-threonine.

Electronic supplementary materialThe online version of this article doi:10.1186-1755-8794-7-4 contains supplementary material, which is available to authorized users.

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Author: Marieke L Kuijjer - Brendy EWM van den Akker - Riet Hilhorst - Monique Mommersteeg - Emilie P Buddingh - Massimo Serra -

Source: https://link.springer.com/







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