Abstract
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 language | English (US) |
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Pages (from-to) | 2386-2397 |
Number of pages | 12 |
Journal | Oncogene |
Volume | 24 |
Issue number | 14 |
DOIs | |
State | Published - Mar 31 2005 |
Externally published | Yes |
Keywords
- 5-aza 2′-deoxycytidine
- Depsipeptide FK228
- Esophageal cancer
- Lung cancer
- TFPI-2
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
- Genetics