4-hydroxynonenal and transforming growth factor-beta1 expression in colon cancer.
In vivo studies on human colon adenocarcinoma showed decreased transforming growth factor-beta1 (TGF-beta1) antiproliferative cytokine content in tumour tissue related to malignancy progression, with a corresponding decrease in lipid peroxidation aldehydic end-product, 4-hydroxynonenal (HNE). The tumour mechanism to escape TGF-beta1-mediated growth inhibition may be due to an altered TGF-beta1 receptor system. Subsequent in vitro analyses showed a differential distribution of TGF-beta1 receptors depending on the human colon cancer cell line considered (CaCo-2 or HT-29): compared to HT-29 cells, CaCo-2 cells showed a decrease of the two main TGF-beta1 receptors, RI and RII. Notwithstanding their partial TGF-beta1 RI and RII deficiency, treatment of CaCo-2 cells with adequate doses of the cytokine (10 ng/ml) was able to induce apoptosis. Of note, co-treatment of these cells with 1 microM HNE increased the apoptotic effect. The constant low concentration of TGF-beta1 in the tumour mass may be related to the low content of antiproliferative HNE observed in colon cancer: the latter phenomenon, which reduces TGF-beta1 production in the tumour area, may represent a favourable condition for neoplastic progression. The enhancement of TGF-beta1-induced apoptosis by HNE in CaCo-2 cells supports this hypothesis. The different transcriptional components regulated by the distinct signaling pathways of these two molecules might be proposed; in particular, crosstalk between the MAPK and the Smad pathway could modulate and co-operate in the transcription of target genes involved in regulation of cell proliferation.
Zanetti
D
D
Department of Clinical and Biological Sciences of the University of Turin, S. Luigi Gonzaga Hospital, Orbassano, Turin 10043, Italy.
Poli
G
G
Vizio
B
B
Zingaro
B
B
Chiarpotto
E
E
Biasi
F
F
D000230:Adenocarcinoma / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D010084:Oxidation-Reduction; D018125:Receptors, Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics*
D000447:Aldehydes; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C027576:4-hydroxy-2-nonenal