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.
Jain
Anshu K
AK
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, 111 TW Alexander Drive, Research Triangle Park, NC 27709, USA.
Moore
Scott M
SM
Yamaguchi
Kiyoshi
K
Eling
Thomas E
TE
Baek
Seung Joon
SJ
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