HIF-1α Induces a Chemoresistance Phenotype in a Non-Hodgkin‘s Lymphoma Cell Line Via up-Regulation of Bcl-_xL

Abstract 5091

Non-Hodgkin's Lymphoma (NHL) is one of the most common cancers in childhood. The development of chemoresistance in tumor cells is one of the principal causes of treatment failure. This resistance has been associated to different mechanisms, being the overexpression of anti-apoptotic proteins such as Bcl-xL. It has been shown that this protein is regulated by the transcription factor HIF-1α, which is overexpressed in several tumors, including NHL, and the overexpression of both proteins may result in resistance to chemotherapy. We investigated the role of HIF-1α in resistance to chemotherapy via the induction of the Bcl-xL expression in NHL cell lines, using a pharmacological modulation of HIF-1α. Our data showed that treating the Ramos cell with ethyl 3, 4-dihydroxybenzoate, the inhibitor of prolylhydroxylase, induces accumulation of HIF-1α and this correlates with an increase of Bcl-xL as well as resistance to apoptosis after the exposition to chemotherapeutics drugs. In contrast, the treatment of Ramos cells with 2-methoxyestradiol, the inhibitor of HIF-1α activity, induced downregulation of the Bcl-xL expression, and this correlates with the sensitization of tumor cells to chemotherapeutic drugs. This data demonstrated that the up-regulation of the anti-apoptotic protein Bcl-xL in NHL cells correlates with HIF-1α expression and activity, through which induces a phenotype of chemoresistance.