TY - JOUR
T1 - Retinoic acid/alpha-interferon combination inhibits growth and promotes apoptosis in mantle cell lymphoma through Akt-dependent modulation of critical targets
AU - Col, Jessica Dal
AU - Mastorci, Katy
AU - Fae, Damiana Antonia
AU - Muraro, Elena
AU - Martorelli, Debora
AU - Inghirami, Giorgio
AU - Dolcetti, Riccardo
PY - 2012/4/1
Y1 - 2012/4/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-11-2505
DO - 10.1158/0008-5472.CAN-11-2505
M3 - Article
C2 - 22311672
AN - SCOPUS:84859396088
VL - 72
SP - 1825
EP - 1835
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 7
ER -