Pathways of retinoic acid- or arsenic trioxide-induced PML/RARalpha catabolism, role of oncogene degradation in disease remission.
Although there is evidence to suggest that PML/RARalpha expression is not the sole genetic event required for the development of acute promyelocytic leukemia (APL), there is little doubt that the fusion protein plays a central role in the initiation of leukemogenesis. The two therapeutic agents, retinoic acid and arsenic, that induce clinical remissions in APL, both target the oncogenic fusion protein, representing the first example of oncogene-directed cancer therapy. This review focuses on the molecular mechanisms accounting for PML/RARalpha degradation. Each drug targets a specific moiety of the fusion protein (RARalpha for retinoic acid, PML for arsenic) to the proteasome. Moreover, both activate a common caspase-dependent cleavage in the PML part of the fusion protein. Specific molecular determinants (the AF2 transactivator domain of RARalpha for retinoic acid and the K160 SUMO-binding site in PML for arsenic) are respectively implicated in RA- or arsenic-triggered catabolism. The respective roles of PML/RARalpha activation versus its catabolism are discussed with respect to differentiation or apoptosis induction in the context of single or dual therapies.
Zhu
J
J
CNRS UPR 9051, Laboratoire associé #11 Comité de Paris de la Ligue Française contre le Cancer, Affiliè à l'Université de Paris VII. Hôpital St. Louis, 1, Av. C. Vellefaux 75475 Paris Cedex 10, France.
Lallemand-Breitenbach
V
V
de Thé
H
H
D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001665:Binding Sites; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D017434:Protein Structure, Tertiary; D012074:Remission Induction; D014212:Tretinoin / Q000494:pharmacology*
D001152:Arsenicals; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D010087:Oxides; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D020169:Caspases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000077237:Arsenic Trioxide