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Inhibition of pituitary tumor‐transforming gene‐1 in thyroid cancer cells by drugs that decrease specificity proteins
Author(s) -
Chintharlapalli Sudhakar,
Papineni Sabitha,
Lee SyngOok,
Lei Ping,
Jin Un Ho,
Sherman Steven I.,
Santarpia Libero,
Safe Stephen
Publication year - 2011
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20738
Subject(s) - biology , gene , cancer research , thyroid , thyroid cancer , cancer , medicine , endocrinology , genetics
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. © 2011 Wiley‐Liss, Inc.