Naslov
C-Jun N-terminal kinase upregulation as a key event in the proapoptotic interaction between transforming growth factor-β 1 and 4-hydroxynonenal in colon mucosa

Autori
Biasi, F. ; Vizio, B. ; Mascia, C. ; Gaia, E. ; Žarković, Neven ; Chiarpotto, E. ; Leonarduzzi, G. ; Poli, G.

Izvornik
Free Radical Medicine and Biology (0891-5849) 41 (2006); 443-454

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
4-hydroxynonenal; apoptosis; colon cancer; HNE; JNK; JNK inhibitors; Smads; TGF-beta1

Sažetak
Cells of colonic mucosa are sensitive to the Smad-mediated growth-inhibitory effect of transforming growth factor-β 1 (TGF-β 1). Another important cell growth inhibitor is the polyunsaturated lipid peroxidation end product, 4-hydroxynonenal (HNE), which triggers apoptosis through c-Jun N-terminal kinase (JNK) activation. Interestingly, a close association between TGF-β 1 and HNE was found in the progression of human colon cancer, with concentration of both molecules inversely related to the malignancy. We investigated the cross talk between Smads and JNK signal transduction pathways in inducing apoptosis. To this purpose TGF-β 1 and HNE were added singly or in combination to CaCo-2 human colon adenocarcinoma cells. The cotreatment induced a marked enhancement of apoptosis and of JNK and Smad4 activities much more than either individual molecule. Cell preincubation with the JNK inhibitor SP600125 significantly prevented JNK and Smad4 enhancement and, subsequently, the cooperative proapoptotic effect was abolished. The primary role of JNK activity in TGF-β 1/HNE cooperative signaling was fully confirmed in a second set of experiments by using JNKi I, a more selective kinase inhibitor. Hence, in tumor cells becoming resistant to TGF-β 1-mediated growth inhibition, increased induction of the remaining TGF-β 1 pathways by interaction with other antiproliferative molecules, such as HNE, could help in inhibiting tumor growth.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti, Kliničke medicinske znanosti

POVEZANOST RADA