Histone deacetylase inhibitors enhance the apoptotic activity of insulin-like growth factor binding protein-3 by blocking PKC-induced IGFBP-3 degradation

Seung Hyun Oh, Young Mi Whang, Hye Young Min, Seung Ho Han, Ju Hee Kang, Ki Hoon Song, Bonnie S. Glisson, Yeul Hong Kim, Ho Young Lee

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Overexpression of insulin-like growth factor binding protein (IGFBP)-3 induces apoptosis of cancer cells. However, preexisting resistance to IGFBP-3 could limit its antitumor activities. This study characterizes the efficacy and mechanism of the combination of recombinant IGFBP-3 (rIGFBP-3) and HDAC inhibitors to overcome IGFBP-3 resistance in a subset of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) cells. The effects of the combination of rIGFBP-3 and a number of HDAC inhibitors on cell proliferation and apoptosis were assessed in vitro and in vivo by using the MTT assay, a flow cytometry-based TUNEL assay, Western blot analyses and the NSCLC xenograft tumor model. Combined treatment with HDAC inhibitors and rIGFBP-3 had synergistic antiproliferative effects accompanied by increased apoptosis rates in a subset of NSCLC and HNSCC cell lines in vitro. Moreover, combined treatment with depsipeptide and rIGFBP-3 completely suppressed tumor growth and increased the apoptosis rate in vivo in H1299 NSCLC xenografts. Evidence suggests that HDAC inhibitors increased the half-life of rIGFBP-3 protein by blocking protein kinase C (PKC)-mediated phosphorylation and degradation of rIGFBP-3. In addition, combined treatment of IGFBP-3 with an HDAC inhibitor facilitates apoptosis through upregulation of rIGFBP-3 stability and Akt signaling inhibition. The ability of HDAC inhibitors to decrease PKC activation may enhance apoptotic activities of rIGFBP-3 in NSCLC cells in vitro and in vivo. These results indicated that combined treatment with HDAC inhibitor and rIGFBP-3 could be an effective treatment strategy for NSCLC and HNSCC with highly activated PKC.

Original languageEnglish
Pages (from-to)2253-2263
Number of pages11
JournalInternational Journal of Cancer
Volume131
Issue number10
DOIs
Publication statusPublished - 2012 Nov 15

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Keywords

  • Akt
  • head and neck squamous cell carcinoma
  • histone deacetylases
  • insulin-like growth factor binding protein-3
  • Non-small cell lung cancer
  • protein kinase C

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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