Caveolin-1-mediated suppression of cyclooxygenase-2 via a beta-catenin-Tcf/Lef-dependent transcriptional mechanism reduced prostaglandin E2 production and survivin expression.
Augmented expression of cyclooxygenase-2 (COX-2) and enhanced production of prostaglandin E(2) (PGE(2)) are associated with increased tumor cell survival and malignancy. Caveolin-1 is a scaffold protein that has been proposed to function as a tumor suppressor in human cancer cells, although mechanisms underlying this ability remain controversial. Intriguingly, the possibility that caveolin-1 regulates the expression of COX-2 has not been explored. Here we show that augmented caveolin-1 expression in cells with low basal levels of this protein, such as human colon cancer (HT29, DLD-1), breast cancer (ZR75), and embryonic kidney (HEK293T) cells reduced COX-2 mRNA and protein levels and beta-catenin-Tcf/Lef and COX-2 gene reporter activity, as well as the production of PGE(2) and cell proliferation. Moreover, COX-2 overexpression or PGE(2) supplementation increased levels of the inhibitor of apoptosis protein survivin by a transcriptional mechanism, as determined by PCR analysis, survivin gene reporter assays and Western blotting. Furthermore, addition of PGE(2) to the medium prevented effects attributed to caveolin-1-mediated inhibition of beta-catenin-Tcf/Lef-dependent transcription. Finally, PGE(2) reduced the coimmunoprecipitation of caveolin-1 with beta-catenin and their colocalization at the plasma membrane. Thus, by reducing COX-2 expression, caveolin-1 interrupts a feedback amplification loop involving PGE(2)-induced signaling events linked to beta-catenin/Tcf/Lef-dependent transcription of tumor survival genes including cox-2 itself and survivin.
Rodriguez
Diego A
DA
Fondo de Investigación Avanzada en Areas Prioritarias, Center for Molecular Studies of the Cell, Departmento de Cirugía, Hospital Clínico, Universidad de Chile, Santiago, Chile.
Tapia
Julio C
JC
Fernandez
Jaime G
JG
Torres
Vicente A
VA
Muñoz
Nicolas
N
Galleguillos
Daniela
D
Leyton
Lisette
L
Quest
Andrew F G
AF
D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077022:Survivin; D014158:Transcription, Genetic / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
C107489:BIRC5 protein, human; D015820:Cadherins; D051242:Caveolin 1; D051034:Inhibitor of Apoptosis Proteins; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D000077022:Survivin; D051176:beta Catenin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone