4-Hydroxynonenal and PPARgamma ligands affect proliferation, differentiation, and apoptosis in colon cancer cells.
PPARgamma ligands inhibit growth and induce apoptosis of various cancer cells. 4-Hydroxynonenal (HNE), a product of lipid peroxidation, inhibits proliferation and induces differentiation or apoptosis in neoplastic cells. The aim of this work was to investigate the effects of PPARgamma ligands (rosiglitazone and 15-deoxy-prostaglandin J2 (15d-PGJ2)) and HNE, alone or in association, on proliferation, apoptosis, differentiation, and growth-related and apoptosis-related gene expression in colon cancer cells (CaCo-2 cells). PPARgamma ligands inhibited cell proliferation (IC50 was 37.47+/-6.6 microM, for 15d-PGJ2, and 170.34+/-20 microM for rosiglitazone). HNE (1 microM) inhibited cell growth by 70%. Apoptosis was induced by 15d-PGJ2 and HNE and, to a minor extent, rosiglitazone. Differentiation was induced by rosiglitazone and by 15d-PGJ2, but not by HNE. PPARgamma ligands inhibited c-myc expression. HNE induced a transitory increase in c-myc expression and a subsequent down-regulation. HNE induced p21 expression, whereas PPARgamma ligands did not. Expression of the bax gene was increased by HNE and 15d-PGJ2, but not by rosiglitazone. No synergism or antagonism was found between HNE and PPARgamma ligands. Both apoptosis and differentiation induction may be responsible for the inhibition of proliferation by PPARgamma ligands; apoptosis and c-myc and p21 expression seem to be involved in the inhibition of proliferation by HNE.
Cerbone
Angelo
A
Istituto di Ricerche Biomediche A Maxer RBM s.p.a., Colleretto Giocosa, Turin, Italy.
Toaldo
Cristina
C
Laurora
Stefano
S
Briatore
Federica
F
Pizzimenti
Stefania
S
Dianzani
Mario U
MU
Ferretti
Carlo
C
Barrera
Giuseppina
G
D000447:Aldehydes / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008024:Ligands; D047495:PPAR gamma / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000235:genetics
C477819:15-deoxyprostaglandin J2; D000447:Aldehydes; D003432:Cross-Linking Reagents; D015853:Cysteine Proteinase Inhibitors; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D051028:bcl-2-Associated X Protein; D000077154:Rosiglitazone; C027576:4-hydroxy-2-nonenal; D015230:Prostaglandin D2