Abstract
Mantle cell lymphoma (MCL) is characterized by a profound deregulation of the mechanisms controlling cell-cycle progression and survival. We herein show that the combination of 9-cis-retinoic acid (RA) and IFN-α induces marked antiproliferative and proapoptotic effects in MCL cells through the modulation of critical targets. Particularly, IFN-α enhances RA-mediated G(0)-G(1) cell accumulation by downregulating cyclin D1 and increasing p27(Kip1) and p21(WAF1/Cip1) protein levels. Furthermore, RA/IFN-α combination also induces apoptosis by triggering both caspases-8 and -9 resulting in Bax and Bak activation. In particular, RA/IFN-α treatment downregulates the antiapoptotic Bcl-xL and Bfl-1 proteins and upregulates the proapoptotic BH3-only Noxa protein. Sequestration of Mcl-1 and Bfl-1 by upregulated Noxa results in the activation of Bid, and the consequent induction of apoptosis is inhibited by Noxa silencing. Noxa upregulation is associated with nuclear translocation of the FOXO3a transcription factor as consequence of RA/IFN-α-induced Akt inhibition. Pharmacologic suppression of Akt, but not of TORC1, increases Noxa protein levels and downregulates Bfl-1 protein supporting the conclusion that the inhibition of the Akt pathway, the resulting FOXO3a activation and Noxa upregulation are critical molecular mechanisms underlying RA/IFN-α-dependent MCL cell apoptosis. These results support the potential therapeutic value of RA/IFN-α combination in MCL management.
Highlights
Mantle cell lymphoma (MCL) is a distinct CD5þ B-cell non–Hodgkin lymphoma (NHL) characterized by the t(11;14)(q13; q32) translocation that leads to overexpression of cyclin D1 and subsequent cyclin D/Rb pathway deregulation [1, 2]
Gene expression profiling of MCL cells has recently shown the dysregulation of several genes/proteins involved in NF-kB, phosphoinositide 3-kinase (PI3K)/Akt, and mTOR signaling pathways, which are all constitutively activated in MCL cells [6,7,8,9]
Taking into account our previous findings indicating that the PI3K/Akt pathway is critical for MCL cell survival and that Akt, but not mTOR, inhibition induces apoptotic responses in MCL [9], we investigated the effects of retinoic acid (RA)/IFN-a treatment on the inherent PI3K/Akt activation
Summary
Mantle cell lymphoma (MCL) is a distinct CD5þ B-cell non–Hodgkin lymphoma (NHL) characterized by the t(11;14)(q13; q32) translocation that leads to overexpression of cyclin D1 and subsequent cyclin D/Rb pathway deregulation [1, 2]. Gene expression profiling of MCL cells has recently shown the dysregulation of several genes/proteins involved in NF-kB, PI3K/Akt, and mTOR signaling pathways, which are all constitutively activated in MCL cells [6,7,8,9]. These findings suggest that a profound alteration of pathways regulating cell survival is likely responsible for the aggressive clinical behavior of MCL, Authors' Affiliations: 1Cancer Bio-Immunotherapy Unit, Department of Medical Oncology, Centro di Riferimento Oncologico, IRCCS - National Cancer Institute, Aviano (PN), Italy; and 2Department of Pathology and CeRMS, University of Torino, Torino, Italy. New therapeutic options need to be explored in patients affected by these lymphomas
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