Hypoxia inducible factor-1α induces chemoresistance phenotype in non-Hodgkin lymphoma cell line via up-regulation of Bcl-_xL

Abstract

Non-Hodgkin 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 with different mechanisms, one being the overexpression of anti-apoptotic proteins such as Bcl-_xL. It has been shown that this protein is regulated by the transcription factor hypoxia inducible factor-1α (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 Bcl-_xL expression in NHL cell lines, using a pharmacological modulation of HIF-1α. Our data showed that treating Ramos cells with ethyl 3,4-dihydroxybenzoate, an inhibitor of prolyl hydroxylase, induces accumulation of HIF-1α and this correlates with an increase of Bcl-_xL as well as resistance to apoptosis after exposure to chemotherapeutics drugs. In contrast, the treatment of Ramos cells with 2-methoxyestradiol, an inhibitor of HIF-1α activity, induced down-regulation of Bcl-_xL expression, and this correlated with the sensitization of tumor cells to chemotherapeutic drugs. These data demonstrate that up-regulation of the anti-apoptotic protein Bcl-_xL in NHL cells correlates with HIF-1α expression and activity, through which a phenotype of chemoresistance is induced.

Keywords::

• HIF-1α
• Bcl-_xL, chemoresistance
• non-Hodgkin lymphoma

Potential conflict of interest

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This study was supported by a Collaborative Research Grant from the National Council of Science and Technology 2008-C01-88004 (CONACYT) (S.H-Y); Mexico Federal Funds Grant HIM/2009/008 (S.H-Y); doctoral scholarship degree grant (M.A.H-L) CONACyT-220662; and miembros del Patronato del HIM (S.H-Y).