Inhibition of pituitary tumor-transforming gene-1 in thyroid cancer cells by drugs that decrease specificity proteins.
Methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate (CDODA-Me) and the corresponding 2-trifluoromethyl analog (CF(3)DODA-Me) are derived synthetically from the triterpenoid glycyrrhetinic acid, a major component of licorice. CDODA-Me and CF(3)DODA-Me inhibited growth of highly invasive ARO, DRO, K-18, and HTh-74 thyroid cancer cells and this was due, in part, to decreased expression of specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4 that are overexpressed in these cells. CDODA-Me and CF(3)DODA-Me also decreased expression of Sp-dependent genes, such as survivin and vascular endothelial growth factor (VEGF), and induced apoptosis. In addition, pituitary tumor-transforming gene-1 (PTTG-1) protein and mRNA levels were also decreased in thyroid cancer cells treated with CDODA-Me or CF(3)DODA-Me and this was accompanied by decreased expression of PTTG-1-dependent c-Myc and fibroblast growth factor-2 (FGF-2) genes. RNA interference studies against Sp1, Sp3, and Sp4 proteins showed that in thyroid cancer cells, PTTG-1 was an Sp-dependent gene. This study demonstrates for the first time that drugs, such as CDODA-Me and CF(3)DODA-Me, that decrease Sp protein expression also downregulate PTTG-1 in thyroid cancer cells and therefore have potential for clinical treatment of thyroid cancer and other endocrine neoplasias where PTTG-1 is a major pro-oncogenic factor.
Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, USA.
Sudhakar
S
Chintharlapalli
Sabitha
S
Papineni
Syng-Ook
SO
Lee
Ping
P
Lei
Un Ho
UH
Jin
Steven I
SI
Sherman
Libero
L
Santarpia
Stephen
S
Safe
D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017931:DNA Primers; D005461:Fluorine / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064249:Securin; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D017931:DNA Primers; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D064249:Securin; C543611:methyl 2-cyano-3,11-dioxo-18beta-olean-1,12-dien-30-oate; C578002:pituitary tumor-transforming protein 1, human; D005461:Fluorine; D006034:Glycyrrhetinic Acid
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