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.

Links

Publisher Full Text

Authors

Dal Col J, Mastorci K, Faè DA, Muraro E, Martorelli D, Inghirami G, Dolcetti R

Institution

Cancer Bio-Immunotherapy Unit, Department of Medical Oncology, Centro di Riferimento Oncologico, IRCCS - National Cancer Institute, Aviano, PN, Italy.

Source

Cancer research 72:7 2012 Apr 1 pg 1825-35

MeSH

Aged
Antineoplastic Combined Chemotherapy Protocols
Apoptosis
Cell Line, Tumor
Cell Proliferation
Female
Forkhead Transcription Factors
Humans
Interferon-alpha
Lymphoma, Mantle-Cell
Male
Middle Aged
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins c-bcl-2
Receptors, Retinoic Acid
Retinoid X Receptors
Tretinoin

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22311672