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

BMC Medical Genomics

Anne-Marie Cleton-Jansen²  Pancras CW Hogendoorn²  Horst Bürger¹  Massimo Serra⁶  Emilie P Buddingh⁴  Monique Mommersteeg⁵  Riet Hilhorst⁵  Brendy EWM van den Akker²  Marieke L Kuijjer³ 

[1] Institute of Pathology, Paderborn/Höxter, Germany;Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2300RC Leiden, The Netherlands;Current affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA;Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands;PamGene International BV, ‘s-Hertogenbosch, The Netherlands;Laboratory of Experimental Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy

关键词: Bone tumor;    Genomic instability;    Gene expression profiling;    Kinome profiling;    Tumor cell lines;    Osteosarcoma;   

Others  :  1090988
DOI  :  10.1186/1755-8794-7-4

 received in 2013-04-24, accepted in 2014-01-14,  发布年份 2014

【 摘 要 】

Background

High-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.

Methods

We 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.

Results

Gene 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.

Conclusions

We 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.

【 授权许可】

   
2014 Kuijjer et al.; licensee BioMed Central Ltd.

【 图 表 】

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