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Published on: July 28, 2010
4-Hydroxynonenal and PPARgamma ligands affect proliferation, differentiation, and apoptosis in colon cancer cells
Angelo Cerbone1, Cristina Toaldo, Stefano Laurora
1Istituto di Ricerche Biomediche A Maxer RBM s.p.a., Colleretto Giocosa, Turin, Italy.
Abstract:
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.
Insights
PPARgamma ligands and 4-hydroxynonenal (HNE) inhibit colon cancer cell growth. Both compounds induce apoptosis, while PPARgamma ligands also promote differentiation, affecting gene expression differently.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands are known to inhibit cancer cell growth and induce apoptosis.
- 4-Hydroxynonenal (HNE), a lipid peroxidation product, also exhibits anti-proliferative and differentiation-inducing or apoptosis-inducing effects on neoplastic cells.
Purpose of the Study:
- To investigate the individual and combined effects of PPARgamma ligands (rosiglitazone, 15-deoxy-prostaglandin J2 [15d-PGJ2]) and HNE on colon cancer cell (CaCo-2) proliferation, apoptosis, and differentiation.
- To analyze the impact of these agents on the expression of growth- and apoptosis-related genes.
Main Methods:
- CaCo-2 cells were treated with PPARgamma ligands (rosiglitazone, 15d-PGJ2) and HNE, alone and in combination.
- Cell proliferation, apoptosis, and differentiation were assessed.
- Gene expression levels for c-myc, p21, and bax were analyzed.
Main Results:
- PPARgamma ligands significantly inhibited cell proliferation, with 15d-PGJ2 being more potent than rosiglitazone. HNE also strongly inhibited cell growth.
- Apoptosis was induced by 15d-PGJ2 and HNE, and to a lesser extent by rosiglitazone. Differentiation was induced by rosiglitazone and 15d-PGJ2, but not HNE.
- PPARgamma ligands downregulated c-myc expression. HNE caused a transient increase followed by downregulation of c-myc and induced p21 expression. HNE and 15d-PGJ2 increased bax expression.
Conclusions:
- Both PPARgamma ligands and HNE are effective in inhibiting colon cancer cell proliferation through distinct mechanisms.
- PPARgamma ligands likely exert their effects via apoptosis and differentiation, impacting c-myc expression.
- HNE's anti-proliferative action involves apoptosis and modulation of c-myc and p21 expression. No synergistic or antagonistic effects were observed between HNE and PPARgamma ligands.
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