Reactivation of suppressed RhoB is a critical step for the inhibition of anaplastic thyroid cancer growth.
Anaplastic thyroid carcinoma (ATC) is a highly aggressive form of the disease for which new therapeutic options are desperately needed. Previously, we showed that the high-affinity peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, RS5444, inhibits cell proliferation of ATC cells via induction of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) (p21). We show here that up-regulation of RhoB is a critical step in PPARgamma-mediated activation of p21-induced cell stasis. Using multiple independently derived ATC cell lines, we found that treatment with RS5444 leads to the up-regulation of RhoB and subsequent activation of p21, and that silencing of RhoB by RNAi blocks the ability of RS5444 to induce p21 and to inhibit cell proliferation. Our results show that transcriptional regulation of RhoB by the nuclear transcription factor PPARgamma is responsible for the induction of p21 mRNA and protein. We further implicate RhoB as a key signaling effector for the growth inhibition of ATC, as treatment with a histone deacetylase inhibitor shown to increase RhoB expression in lung cancer cells caused the up-regulation of RhoB in ATC cells accompanied by increased expression of p21 and inhibition of cell proliferation; this effect occurred even in ATC cells that were unresponsive to RS5444 due to a lack of expression of PPARgamma. Our results implicate RhoB as a novel intermediate in critical signaling pathways and as an additional target for therapeutic intervention in ATC.
Marlow
Laura A
LA
Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida 32224, USA.
Reynolds
Lisa A
LA
Cleland
Alan S
AS
Cooper
Simon J
SJ
Gumz
Michelle L
ML
Kurakata
Shinichi
S
Fujiwara
Kosaku
K
Zhang
Ying
Y
Sebo
Thomas
T
Grant
Clive
C
McIver
Bryan
B
Wadsworth
J Trad
JT
Radisky
Derek C
DC
Smallridge
Robert C
RC
Copland
John A
JA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D002455:Cell Division; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013489:Suppression, Genetic; D045162:Thiazolidinediones / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D014183:Transplantation, Heterologous; D020743:rhoB GTP-Binding Protein / Q000235:genetics*
D000970:Antineoplastic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D020743:rhoB GTP-Binding Protein; C510342:efatutazone