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Sequential 5-Aza 2′-deoxycytidine/depsipeptide FK228 treatment induces tissue factor pathway inhibitor 2 (TFPI-2) expression in cancer cells

Oncogene volume 24, pages 2386–2397 (2005)Cite this article

Abstract

cDNA arrays were used to examine gene induction in CALU-6 and H460 lung cancer cells mediated by sequential 5-aza 2′-deoxycytidine (DAC)/depsipeptide FK228 (DP) exposure in order to identify translational end points for clinical trials evaluating these agents. In both cell lines, sequential DAC/DP treatment induced expression of tissue factor pathway inhibitor-2 (TFPI-2), an inhibitor of Factor VII: tissue factor signal transduction known to diminish the malignant phenotype of cancer cells. TFPI-2 expression was diminished or absent in 16 of 32 cell lines established from thoracic malignancies. Sequential DAC/DP treatment induced TFPI-2 in cancer cells deficient for TFPI-2 expression in the basal state. Promoter methylation coincided with loss of TFPI-2 expression in a number of cancer lines. TFPI-2 promoter methylation was observed in one of five pulmonary adenocarcinomas, and seven of seven esophageal adenocarcinomas, but not corresponding normal tissues. DP enhanced acetylation of TFPI-2-associated histones in CALU-6 cells. DP or PDBU, alone, induced TFPI-2 expression in cancer cells deficient for TFPI-2 expression in the absence of promoter methylation. In these cells, DP-mediated TFPI-2 induction was abrogated by calphostin. Induction of TFPI-2 by distinct, yet cooperative mechanisms involving chromatin remodeling and PKC signaling strengthens the preclinical rationale for sequential administration of DNA demethylating agents and HDAC inhibitors in cancer patients. Furthermore, induction of TFPI-2 may be a useful surrogate marker of treatment response in individuals receiving sequential DAC/DP infusions.

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Authors and Affiliations

  1. Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Federico A Steiner, Julie A Hong, Maria R Fischette, Zong-Sheng Guo, G Aaron Chen, Todd S Weiser, Edmund S Kassis, Dao M Nguyen & David S Schrump

  2. Thoracic Surgery Section, University of Michigan Medical Center, Ann Arbor, MI, USA

    David G Beer

  3. Medical Oncology Clinical Research Unit, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Sunmin Lee & Jane B Trepel

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  1. Federico A Steiner
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Steiner, F., Hong, J., Fischette, M. et al. Sequential 5-Aza 2′-deoxycytidine/depsipeptide FK228 treatment induces tissue factor pathway inhibitor 2 (TFPI-2) expression in cancer cells. Oncogene 24, 2386–2397 (2005). https://doi.org/10.1038/sj.onc.1208376

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