Retinoic Acid/Alpha-Interferon Combination Inhibits Growth and Promotes Apoptosis in Mantle Cell Lymphoma through Akt-Dependent Modulation of Critical Targets

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-a induces marked antiproliferative and proapoptotic effects in MCL cells through the modulation of critical targets. Particularly, IFN-a enhances RA-mediated G 0 -G 1 cell accumulation by downregulating cyclin D1 and increasing p27Kip1 and p21 WAF1/Cip1 protein levels. Furthermore, RA/IFN-a combination also induces apoptosis by triggering both caspases-8 and -9 resulting in Bax and Bak activation. In particular, RA/IFN-a 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-a-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-a-dependent MCL cell apoptosis. These results support the potential therapeutic value of RA/IFN-a combination in MCL management. Cancer Res; 72(7); 1825-35. Ó2012 AACR.

Phospholipid scramblase 1 as a critical node at the crossroad between autophagy and apoptosis in mantle cell lymphoma

“…Previously, we demonstrated that RA/IFN-α treatment induces apoptosis in MCL cells through the inhibition of the PI3-K/Akt pathway [24]. Given the significance of this signalling in the cross-talk between apoptosis and autophagy [31, 32], we investigated the possible relationship between RA/IFN-α-induced cell death and autophagy in MCL cells.…”

“…Aiming at this goal, we have exploited the features of MCL cell apoptosis induced by the combination of 9- cis -retinoic acid (RA) and Interferon(IFN)-α [24], two drugs that may stimulate both pro-apoptotic and autophagic effects in different cellular backgrounds, including lymphocytes [25, 26]. In particular, gene expression profiling approach identified phospholipid scramblase 1 (PLSCR1) as one of the pro-apoptotic genes significantly up-regulated by RA/IFN-α treatment in different MCL cell lines.…”

Expression of vaccinia-related kinase 1 (VRK1) accelerates cell proliferation but overcomes cell adhesion mediated drug resistance (CAM-DR) in multiple myeloma

“…The A c c e p t e d M a n u s c r i p t elevation and it is associated with cell-cycle arrest (9,35,36) . Our study, for the first time, demonstrated that the negative correlation between VRK1 and p27 kip1 expression might be the reason for cell cycle arrest and CAM-DR in MM cells.…”

A RXR Ligand 6-OH-11-O-Hydroxyphenanthrene with Antitumour Properties Enhances (−)-Epigallocatechin-3-gallate Activity in Three Human Breast Carcinoma Cell Lines

“…Both EGCG and retinoids have been demonstrated to activate Foxo3a: in Trastuzumab-resistant HER2-driven breast cancer cells [49] and in ER α -positive breast cancer cells [50] the activation of Foxo3a by EGCG played an important role in the resulting cytotoxicity: all samples treated with EGCG + IIF and IIF alone for 24 h showed a significant increase in Foxo3a RNA expression. Retinoids could switch Foxo3a to the nucleus and trigger apoptosis: Foxo3a is a key molecule in ATRA action on acute promyelocytic leukaemia cells [51] as well as RA and IFN- α in mantle cell lymphoma [52]. The different mechanisms underlying Foxo3a activation might be related to the different biomolecular characteristics of MCF-7, MCF-7TAM, and MDA-MB-231 cells.…”