Soft tissue sarcoma cells are highly sensitive to AKT blockade: A role for p53-independent up-regulation of GADD45α

Quan Sheng Zhu, Wenhong Ren, Borys Korchin, Guy Lahat, Adam Dicker, Yiling Lu, Gordon Mills, Raphael E. Pollock, Dina Lev

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

The AKT signaling pathway is activated in soft tissue sarcoma (STS). However, AKT blockade has not yet been studied as a potential targeted therapeutic approach. Here, we examined the in vitro and in vivo effects of AKT inhibition in STS cells. Western blot analysis was used to evaluate the expression of AKT pathway components and the effect of AKT stimulation and inhibition on their phosphorylation. Cell culture assays were used to assess the effect of AKT blockade (using a phosphatidylinositol 3-kinase inhibitor and a specific AKT inhibitor) on STS cell growth, cell cycle, and apoptosis. Oligoarrays were used to determine gene expression changes in response to AKT inhibition. Reverse transcription-PCR was used for array validation. Specific small inhibitory RNA was used to knockdown GADD45α. Human STS xenografts in nude mice were used for in vivo studies, and immunohistochemistry was used to assess the effect of treatment on GADD45α expression, proliferation, and apoptosis. Multiple STS cell lines expressed activated AKT. AKT inhibition decreased STS downstream target phosphorylation and growth in vitro; G 2 cell cycle arrest and apoptosis were also observed. AKT inhibition induced GADD45α mRNA and protein expression in all STS cells treated independent of p53 mutational status. GADD45α knockdown attenuated the G2 arrest induced by AKT inhibition. In vivo, AKT inhibition led to decreased STS xenograft growth. AKT plays a critical role in survival and proliferation of STS cells. Modulation of AKT kinase activity may provide a novel molecularly based strategy for STS-targeted therapies.

Original languageEnglish (US)
Pages (from-to)2895-2903
Number of pages9
JournalCancer Research
Volume68
Issue number8
DOIs
StatePublished - Apr 15 2008
Externally publishedYes

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Sarcoma
Up-Regulation
Apoptosis
Heterografts
Growth
Phosphorylation
Phosphatidylinositol 3-Kinase
Gastrin-Secreting Cells
Cell Cycle Checkpoints
Nude Mice
Reverse Transcription
Cell Cycle
Phosphotransferases
Therapeutics
Cell Culture Techniques
Western Blotting
Immunohistochemistry
RNA
Gene Expression
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Soft tissue sarcoma cells are highly sensitive to AKT blockade : A role for p53-independent up-regulation of GADD45α. / Zhu, Quan Sheng; Ren, Wenhong; Korchin, Borys; Lahat, Guy; Dicker, Adam; Lu, Yiling; Mills, Gordon; Pollock, Raphael E.; Lev, Dina.

In: Cancer Research, Vol. 68, No. 8, 15.04.2008, p. 2895-2903.

Research output: Contribution to journalArticle

Zhu, Quan Sheng ; Ren, Wenhong ; Korchin, Borys ; Lahat, Guy ; Dicker, Adam ; Lu, Yiling ; Mills, Gordon ; Pollock, Raphael E. ; Lev, Dina. / Soft tissue sarcoma cells are highly sensitive to AKT blockade : A role for p53-independent up-regulation of GADD45α. In: Cancer Research. 2008 ; Vol. 68, No. 8. pp. 2895-2903.
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abstract = "The AKT signaling pathway is activated in soft tissue sarcoma (STS). However, AKT blockade has not yet been studied as a potential targeted therapeutic approach. Here, we examined the in vitro and in vivo effects of AKT inhibition in STS cells. Western blot analysis was used to evaluate the expression of AKT pathway components and the effect of AKT stimulation and inhibition on their phosphorylation. Cell culture assays were used to assess the effect of AKT blockade (using a phosphatidylinositol 3-kinase inhibitor and a specific AKT inhibitor) on STS cell growth, cell cycle, and apoptosis. Oligoarrays were used to determine gene expression changes in response to AKT inhibition. Reverse transcription-PCR was used for array validation. Specific small inhibitory RNA was used to knockdown GADD45α. Human STS xenografts in nude mice were used for in vivo studies, and immunohistochemistry was used to assess the effect of treatment on GADD45α expression, proliferation, and apoptosis. Multiple STS cell lines expressed activated AKT. AKT inhibition decreased STS downstream target phosphorylation and growth in vitro; G 2 cell cycle arrest and apoptosis were also observed. AKT inhibition induced GADD45α mRNA and protein expression in all STS cells treated independent of p53 mutational status. GADD45α knockdown attenuated the G2 arrest induced by AKT inhibition. In vivo, AKT inhibition led to decreased STS xenograft growth. AKT plays a critical role in survival and proliferation of STS cells. Modulation of AKT kinase activity may provide a novel molecularly based strategy for STS-targeted therapies.",
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