Antitumor effect of retinoic acid receptor-beta2 associated with suppression of cyclooxygenase-2.
Retinoic acid receptor-beta2 (RAR-beta2) is a putative tumor suppressor gene in various cancers. To determine the underlying molecular mechanisms, we transfected RAR-beta2 cDNA into esophageal cancer TE-1 and TE-8 cells and found that RAR-beta2 suppressed tumor cell growth in vitro and tumor formation in nude mice in TE-8 cells, whereas the stable transfection of RAR-beta2 did not restore retinoid sensitivity or inhibit tumor formation in nude mouse in TE-1 cells. Molecularly, we revealed that RAR-beta2 antitumor activity was associated with expression and suppression of cyclooxygenase-2 (COX-2) in these tumor cell lines. Moreover, antisense RAR-beta2 cDNA induced COX-2 expression in TE-3 cells. Furthermore, when COX-2 expression is first blocked by using antisense COX-2 expression vector, the effect of RAR-beta2 is diminished in these tumor cells. In addition, we analyzed expression of RAR-beta2 and COX-2 mRNA in tissue specimens and found that RAR-beta2 expression is associated with low levels of COX-2 expression in esophageal cancer tissues. Induction of RAR-beta2 expression in oral leukoplakia tissues after the patients treated with 13-cis RA correlated with a reduction in COX-2 expression and clinical response. Our findings indicate that some of RAR-beta2 antitumor activities are mediated by suppression of COX-2 expression in some of these esophageal cancer cells. After correlating antitumor effect of RAR-beta2 with COX-2 expression in the published studies, we also found the association. Thus, further studies will determine whether manipulation of COX-2 expression in different cancers can antagonize RAR-beta2 activity.
Song
Shumei
S
Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Guan
Baoxiang
B
Men
Taoyan
T
Hoque
Ashraful
A
Lotan
Reuben
R
Xu
Xiao-Chun
XC
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002470:Cell Survival; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D018076:DNA, Complementary / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000517:prevention & control*; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D014162:Transfection
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D018076:DNA, Complementary; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; C540966:retinoic acid receptor, beta2, human