Efectos de componentes del lumen intestinal sobre células de adenocarcinoma de colon humano. Apoptosis inducida por ácidos biliares y regulación de la transcripción génica por butirato

Abstract

Environmental factors are strongly involved in the development of colon cancer. Among them, diet and nutritional habits constitute the most determinant causes in the appearance of sporadic colorectal cancer. The continuous exposure to high concentrations of bile acids in individuals with a fat-rich diet leads to DNA damage and may allow selective growth of cells resistant to the cytotoxic effects of these agents, increasing the risk of tumor development. In this regard, we have studied the effect of DCA and CDCA treatments in butyrate-sensitive BCS-TC2 human colon adenocarcinoma cells, as well as in butyrate-resistant BCS-TC2.BR2 cells. We have confirmed that these bile acids promote cell death in both cell lines, being this effect stronger in BCS-TC2 cells. DCA and CDCA trigger apoptosis after short treatment times (< 2h), as observed by several characteristic apoptotic features, such as cell detachment, internucleosomal DNA degradation, caspase activation and loss of membrane asymmetry. We have confirmed that these events occur in BCS-TC2 cells through the activation of different membrane-associated enzymes [NAD(P)H oxidases and PLA2] which leads to an increase of reactive oxygen species that eventually triggers the mitochondrial apoptotic pathway. The activation of caspase-3 by the apoptosome activates Bax via cleavage of Bcl-2, thus generating a feedback loop that amplifies the apoptotic signal. On the other hand, we have observed that the mechanisms of apoptosis triggered by bile acids in butyrate-resistant cells are similar to that observed in butyrate-sensitive cells. However, BCS-TC2.BR2 cells express higher levels of the antiapoptotic protein Bcl-2 that prevent the activation of Bax. Thus, resistant cells overcome the proapoptotic feedback loop observed in BCS-TC2 cells...