Retinoic acid/alpha-interferon combination inhibits growth and promotes apoptosis in mantle cell lymphoma through Akt-dependent modulation of critical targets.
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.
Cancer Bio-Immunotherapy Unit, Department of Medical Oncology, Centro di Riferimento Oncologico, IRCCS - National Cancer Institute, Aviano, PN, Italy.
Jessica
J
Dal Col
Katy
K
Mastorci
Damiana Antonia
DA
Faè
Elena
E
Muraro
Debora
D
Martorelli
Giorgio
G
Inghirami
Riccardo
R
Dolcetti
D000368:Aged; D000077556:Alitretinoin; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage*; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D018168:Receptors, Retinoic Acid / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors / Q000502:physiology; D014212:Tretinoin / Q000008:administration & dosage*
C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D016898:Interferon-alpha; C498702:PMAIP1 protein, human; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D000077556:Alitretinoin; D014212:Tretinoin; D051057:Proto-Oncogene Proteins c-akt