Transcriptional and posttranslational regulation of insulin-like growth factor binding protein-3 by Akt3

Quanri Jin, Hyo Jong Lee, Hye Young Min, John K endal Smith, Su J ung Hwang, Young M i Whang, Woo Young Kim, Yeul Hong Kim, Ho Young Lee

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8 Citations (Scopus)

Abstract

Insulin-like growth factor (IGF)-dependent and -independent antitumor activities of insulin-like growth factor binding protein-3 (IGFBP-3) have been proposed in human non-small cell lung cancer (NSCLC) cells. However, the mechanism underlying regulation of IGFBP-3 expression in NSCLC cells is not well understood. In this study, we show that activation of Akt, especially Akt3, plays a major role in the mRNA expression and protein stability of IGFBP-3 and thus antitumor activities of IGFBP-3 in NSCLC cells. When Akt was activated by genomic or pharmacologic approaches, IGFBP-3 transcription and protein stability were decreased. Conversely, suppression of Akt increased IGFBP-3 mRNA levels and protein stability in NSCLC cell lines. Characterization of the effects of constitutively active form of each Akt subtype (HA-Akt-DD) on IGFBP-3 expression in NSCLC cells and a xenograft model indicated that Akt3 plays a major role in the Akt-mediated regulation of IGFBP-3 expression and thus suppression of Akt effectively enhances the antitumor activities of IGFBP-3 in NSCLC cells with Akt3 overactivation. Collectively, these data suggest a novel function of Akt3 as a negative regulator of IGFBP-3, indicating the possible benefit of a combined inhibition of IGFBP-3 and Akt3 for the treatment of patients with NSCLC.

Original languageEnglish
Pages (from-to)2232-2243
Number of pages12
JournalCarcinogenesis
Volume35
Issue number10
DOIs
Publication statusPublished - 2014 Oct 1

ASJC Scopus subject areas

  • Medicine(all)

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    Jin, Q., Lee, H. J., Min, H. Y., Smith, J. K. E., Hwang, S. J. U., Whang, Y. M. I., Kim, W. Y., Kim, Y. H., & Lee, H. Y. (2014). Transcriptional and posttranslational regulation of insulin-like growth factor binding protein-3 by Akt3. Carcinogenesis, 35(10), 2232-2243. https://doi.org/10.1093/carcin/bgu129