Drug-induced expression of nonsteroidal anti-inflammatory drug-activated gene/macrophage inhibitory cytokine-1/prostate-derived factor, a putative tumor suppressor, inhibits tumor growth.
A common in vitro response for many chemopreventive and antitumor agents, including some cyclooxygenase inhibitors, is the increased expression of nonsteroidal anti-inflammatory drug-activated gene (NAG)-1/macrophage inhibitory cytokine (MIC)-1/prostate-derived factor (PDF). The experimental anticancer drug 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F203) was a potent inducer of NAG-1 expression, and in MCF-7 cells, it inhibited cell growth and induced apoptosis. NAG-1 small interfering RNA blocked NAG-1 expression and 5F203-induced apoptosis in MCF-7 cells, indicating that NAG-1 may mediate the apoptosis and anticancer activity. One mechanism by which 5F203 increases NAG-1 expression is by increasing the stability of NAG-1 mRNA, dependent of de novo protein synthesis. Extracellular signal-regulated kinase (ERK) 1/2 phosphorylation was increased by 5F203, and inhibition of ERK1/2 phosphorylation abolished the induction of NAG-1 protein expression and increased the stability of NAG-1 mRNA. Thus, 5F203 regulates NAG-1 expression by a unique mechanism compared with other drugs. A mouse orthotopic mammary tumor model was used to determine whether 5F203 increased NAG-1 expression in vivo and suppressed tumor growth. Treatment of the mice with Phortress, the prodrug of 5F203, increased the in vivo expression of NAG-1 as measured by real-time reverse transcription-polymerase chain reaction from RNA obtained by needle biopsy, and the expression correlated with a reduction of tumor volume. These results confirm that NAG-1 suppresses tumor growth, and its in vivo expression can be controlled by treating mice with anticancer drugs, such as Phortress. Drugs that target NAG-1 could lead to a unique strategy for the development of chemotherapeutic and chemopreventive agents.
Martinez
Jeanelle M
JM
Laboratories of Molecular Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
Sali
Tina
T
Okazaki
Ryuji
R
Anna
Colleen
C
Hollingshead
Melinda
M
Hose
Curtis
C
Monks
Anne
A
Walker
Nigel J
NJ
Baek
Seung Joon
SJ
Eling
Thomas E
TE
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D003609:Dactinomycin / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D015870:Gene Expression / Q000187:drug effects*; D055436:Growth Differentiation Factor 15; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D013491:Suppressor Factors, Immunologic / Q000096:biosynthesis* / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000187:drug effects
C425784:2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D016207:Cytokines; C526140:GDF15 protein, human; C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D013491:Suppressor Factors, Immunologic; D013844:Thiazoles; D003609:Dactinomycin; D003513:Cycloheximide; D048049:Extracellular Signal-Regulated MAP Kinases