title: Subversion of the Bcl-2 life/death switch in cancer development and therapy.
abstract: The Bcl-2 protein family, which largely determines commitment to apoptosis, has central roles in tumorigenesis and chemoresistance. Its three factions of interacting proteins include the BH3-only proteins (e.g., Bim, Puma, Bad, Noxa), which transduce diverse cytotoxic signals to the mammalian pro-survival proteins (Bcl-2, Bcl-x(L), Bcl-w, Mcl-1, A-1), whereas Bax and Bak, when freed from pro-survival constraint, provoke the mitochondrial permeabilization that triggers apoptosis. We have discovered unexpected specificity in their interactions. Only Bim and Puma, which mediate multiple cytotoxic signals, engage all the pro-survival proteins. Noxa and Bad instead bind subsets and cooperate in killing, indicating that apoptosis requires neutralization of different pro-survival subsets. Furthermore, Mcl-1 and Bcl-x(L), but not Bcl-2, directly sequester Bak in healthy cells, and Bak is freed only when BH3-only proteins neutralize both its guards. BH3-only proteins such as Bim are tumor suppressors and mediate many of the cytotoxic signals from anticancer agents. Hence, compounds mimicking them may prove valuable for therapy. Indeed, the recently described ABT-737 is a promising "BH3 mimetic" of Bad. We find that, like Bad, ABT-737 kills cells efficiently only if Mcl-1 is absent or down-regulated. Thus, manipulation of apoptosis by targeting the Bcl-2 family has exciting potential for cancer treatment.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
authors.forename: J M
authors.initials: JM
authors.lastname: Adams
authors.forename: D C S
authors.initials: DC
authors.lastname: Huang
authors.forename: A
authors.initials: A
authors.lastname: Strasser
authors.forename: S
authors.initials: S
authors.lastname: Willis
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.forename: A
authors.initials: A
authors.lastname: Wei
authors.forename: M
authors.initials: M
authors.lastname: van Delft
authors.forename: J I
authors.initials: JI
authors.lastname: Fletcher
authors.forename: H
authors.initials: H
authors.lastname: Puthalakath
authors.forename: J
authors.initials: J
authors.lastname: Kuroda
authors.forename: E M
authors.initials: EM
authors.lastname: Michalak
authors.forename: P N
authors.initials: PN
authors.lastname: Kelly
authors.forename: P
authors.initials: P
authors.lastname: Bouillet
authors.forename: A
authors.initials: A
authors.lastname: Villunger
authors.forename: L
authors.initials: L
authors.lastname: O'Reilly
authors.forename: M L
authors.initials: ML
authors.lastname: Bath
authors.forename: D P
authors.initials: DP
authors.lastname: Smith
authors.forename: A
authors.initials: A
authors.lastname: Egle
authors.forename: A W
authors.initials: AW
authors.lastname: Harris
authors.forename: M
authors.initials: M
authors.lastname: Hinds
authors.forename: P
authors.initials: P
authors.lastname: Colman
authors.forename: S
authors.initials: S
authors.lastname: Cory
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001713:Biphenyl Compounds / Q000494:pharmacology; D015195:Drug Design; D019254:Genes, bcl-2; D006801:Humans; D008954:Models, Biological; D018716:Molecular Mimicry; D009369:Neoplasms / Q000188:drug therapy* / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides