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

Federico A. Steiner, Julie A. Hong, Maria R. Fischette, David G. Beer, Zong Sheng Guo, G. Aaron Chen, Todd S. Weiser, Edmund S. Kassis, Dao M. Nguyen, Sunmin Lee, Jane B. Trepel, David S. Schrump

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


cDNA arrays were used to examine gene induction in CALU-6 and H460 lung cancer cells mediated by sequential 5-aza 2′-deoxycytidine (BAC)/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 indnced TFPI-2 in cancer eels 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-mediaied 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 UDAC 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.

Original languageEnglish (US)
Pages (from-to)2386-2397
Number of pages12
Issue number14
StatePublished - Mar 31 2005
Externally publishedYes


  • 5-aza 2′-deoxycytidine
  • Depsipeptide FK228
  • Esophageal cancer
  • Lung cancer
  • TFPI-2

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics


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