Retinoic acid/alpha-interferon combination inhibits growth and promotes apoptosis in mantle cell lymphoma through Akt-dependent modulation of critical targets

Dal Col, Jessica, Mastorci, Katy, Fae, Damiana Antonia, Muraro, Elena, Martorelli, Debora, Inghirami, Giorgio and Dolcetti, Riccardo (2012) Retinoic acid/alpha-interferon combination inhibits growth and promotes apoptosis in mantle cell lymphoma through Akt-dependent modulation of critical targets. Cancer Research, 72 7: 1825-1835. doi:10.1158/0008-5472.CAN-11-2505


Author Dal Col, Jessica
Mastorci, Katy
Fae, Damiana Antonia
Muraro, Elena
Martorelli, Debora
Inghirami, Giorgio
Dolcetti, Riccardo
Title Retinoic acid/alpha-interferon combination inhibits growth and promotes apoptosis in mantle cell lymphoma through Akt-dependent modulation of critical targets
Journal name Cancer Research   Check publisher's open access policy
ISSN 0008-5472
1538-7445
Publication date 2012-04-01
Year available 2012
Sub-type Article (original research)
DOI 10.1158/0008-5472.CAN-11-2505
Open Access Status Not yet assessed
Volume 72
Issue 7
Start page 1825
End page 1835
Total pages 11
Place of publication Philadelphia, PA, United States
Publisher American Association for Cancer Research
Language eng
Formatted 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 G0-G1 cell accumulation by downregulating cyclin D1 and increasing p27Kip1 and p21WAF1/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.
Keyword Oncology
Oncology
ONCOLOGY
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 10301
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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