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.
4-hydroxynonenal and transforming growth factor-beta1 expression in colon cancer.
POLI, Giuseppe;VIZIO, Barbara;CHIARPOTTO, Elena Maria;BIASI, Fiorella
2003-01-01
Abstract
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.
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