Selective nonsteroidal anti-inflammatory drugs induce thymosin beta-4 and alter actin cytoskeletal organization in human colorectal cancer cells.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their anti-inflammatory effects and have been shown to have chemopreventive effects as well. NSAIDs inhibit cyclooxygenase (COX) activity to exert their anti-inflammatory effects, but it is not clear whether their antitumorigenic ability is through COX inhibition. Using subtractive hybridization, we previously identified a novel member of the transforming growth factor-beta superfamily that has antitumorigenic activity from indomethacin-treated HCT-116 human colorectal cancer cells. On further investigation of this library, we now report the identification of a new cDNA corresponding to the thymosin beta-4 gene. Thymosin beta-4 is a small peptide that is known for its actin-sequestering function, and it is associated with the induction of angiogenesis, accelerated wound healing, and metastatic potential of tumor cells. However, only selective NSAIDs induce thymosin beta-4 expression in a time- and concentration-dependent manner. For example, indomethacin and SC-560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole] induce thymosin beta-4 expression whereas sulindac sulfide does not. We show that selective NSAIDs induce actin cytoskeletal reorganization, a precursory step to many dynamic processes regulating growth and motility including tumorigenesis. This is the first report to link thymosin beta-4 induction with NSAIDs. These data suggest that NSAIDs alter the expression of a diverse number of genes and provide new insights into the chemopreventive and biological activity of these drugs.
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, 111 TW Alexander Drive, Research Triangle Park, NC 27709, USA.
Anshu K
AK
Jain
Scott M
SM
Moore
Kiyoshi
K
Yamaguchi
Thomas E
TE
Eling
Seung Joon
SJ
Baek
D000199:Actins / Q000378:metabolism*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015152:Blotting, Northern; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics; D003599:Cytoskeleton / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005455:Fluorescent Antibody Technique; D055436:Growth Differentiation Factor 15; D006801:Humans; D007202:Indicators and Reagents; D007213:Indomethacin / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013947:Thymosin / Q000096:biosynthesis* / Q000235:genetics; D000099201:Thymosin beta(4)
D000199:Actins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D015232:Dinoprostone; D055436:Growth Differentiation Factor 15; D007202:Indicators and Reagents; D007213:Indomethacin; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D012334:RNA, Neoplasm; D013947:Thymosin; D000099201:Thymosin beta(4); C526140:GDF15 protein, human; C115461:SC 560