Synergistic antitumor effect of the activated PPARgamma and retinoid receptors on human osteosarcoma.
OBJECTIVE
Osteosarcoma is the most common primary malignancy of bone. The long-term survival of osteosarcoma patients hinges on our ability to prevent and/or treat recurrent and metastatic lesions. Here, we investigated the activation of peroxisome proliferator-activated receptor gamma (PPARgamma) and retinoid receptors as a means of differentiation therapy for human osteosarcoma.


METHODS
We examined the endogenous expression of PPARgamma and retinoid receptors in a panel of osteosarcoma cells. Ligands or adenovirus-mediated overexpression of these receptors were tested to inhibit proliferation and induce apoptosis of osteosarcoma cells. Osteosarcoma cells overexpressing the receptors were introduced into an orthotopic tumor model. The effect of these ligands on osteoblastic differentiation was further investigated.


RESULTS
Endogenous expression of PPARgamma and isotypes of retinoic acid receptor (RAR) and retinoid X receptor (RXR) is detected in most osteosarcoma cells. Troglitazone, 9-cis retinoic acid (RA), and all-trans RA, as well as overexpression of PPARgamma, RARalpha, and RXRalpha, inhibit osteosarcoma cell proliferation and induce apoptosis. A synergistic inhibitory effect on osteosarcoma cell proliferation is observed between troglitazone and retinoids, as well as with the overexpression pairs of PPARgamma/RARalpha, or PPARgamma/RXRalpha. Overexpression of PPARgamma, RARalpha, RXRalpha, or in combinations inhibits osteosarcoma tumor growth and cell proliferation in vivo. Retinoids (and to a lesser extent, troglitazone) are shown to promote osteogenic differentiation of osteosarcoma cells and mesenchymal stem cells.


CONCLUSIONS
Activation of PPARgamma, RARalpha, and RXRalpha may act synergistically on inhibiting osteosarcoma cell proliferation and tumor growth, which is at least partially mediated by promoting osteoblastic differentiation of osteosarcoma cells.
He
Bai-Cheng
BC
Key Laboratory of Diagnostic Medicine designated by the Chinese Ministry of Education and the Affiliated Hospitals, China.
Chen
Liang
L
Zuo
Guo-Wei
GW
Zhang
Wenli
W
Bi
Yang
Y
Huang
Jiayi
J
Wang
Yi
Y
Jiang
Wei
W
Luo
Qing
Q
Shi
Qiong
Q
Zhang
Bing-Qiang
BQ
Liu
Bo
B
Lei
Xia
X
Luo
Jinyong
J
Luo
Xiaoji
X
Wagner
Eric R
ER
Kim
Stephanie H
SH
He
Connie J
CJ
Hu
Yawen
Y
Shen
Jikun
J
Zhou
Qixin
Q
Rastegar
Farbod
F
Deng
Zhong-Liang
ZL
Luu
Hue H
HH
He
Tong-Chuan
TC
Haydon
Rex C
RC
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000494:pharmacology
D000970:Antineoplastic Agents; D047495:PPAR gamma; C000607071:RARA protein, human; D012333:RNA, Messenger; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D014212:Tretinoin; D008156:Luciferases