Sequential 5-Aza 2'-deoxycytidine/depsipeptide FK228 treatment induces tissue factor pathway inhibitor 2 (TFPI-2) expression in cancer cells.
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.
Steiner
Federico A
FA
Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1201, USA.
Hong
Julie A
JA
Fischette
Maria R
MR
Beer
David G
DG
Guo
Zong-Sheng
ZS
Chen
G Aaron
GA
Weiser
Todd S
TS
Kassis
Edmund S
ES
Nguyen
Dao M
DM
Lee
Sunmin
S
Trepel
Jane B
JB
Schrump
David S
DS
D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D000077209:Decitabine; D047630:Depsipeptides / Q000494:pharmacology*; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology
D017931:DNA Primers; D047630:Depsipeptides; D006023:Glycoproteins; C021240:tissue-factor-pathway inhibitor 2; D000077209:Decitabine; C087123:romidepsin; D001374:Azacitidine