A short Nur77-derived peptide converts Bcl-2 from a protector to a killer.
Bcl-2 can be converted into a proapoptotic molecule by nuclear receptor Nur77. However, the development of Bcl-2 converters as anticancer therapeutics has not been explored. Here we report the identification of a Nur77-derived Bcl-2-converting peptide with 9 amino acids (NuBCP-9) and its enantiomer, which induce apoptosis of cancer cells in vitro and in animals. The apoptotic effect of NuBCPs and their activation of Bax are not inhibited but rather potentiated by Bcl-2. NuBCP-9 and its enantiomer bind to the Bcl-2 loop, which shares the characteristics of structurally adaptable regions with many cancer-associated and signaling proteins. NuBCP-9s act as molecular switches to dislodge the Bcl-2 BH4 domain, exposing its BH3 domain, which in turn blocks the activity of antiapoptotic Bcl-X(L).
Cancer Center, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Siva Kumar
SK
Kolluri
Xiuwen
X
Zhu
Xin
X
Zhou
Bingzhen
B
Lin
Ya
Y
Chen
Kai
K
Sun
Xuefei
X
Tian
James
J
Town
Xihua
X
Cao
Feng
F
Lin
Dayong
D
Zhai
Shinichi
S
Kitada
Frederick
F
Luciano
Edmond
E
O'Donnell
Yu
Y
Cao
Feng
F
He
Jialing
J
Lin
John C
JC
Reed
Arnold C
AC
Satterthwait
Xiao-kun
XK
Zhang
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D013237:Stereoisomerism; D013997:Time Factors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D051023:BH3 Interacting Domain Death Agonist Protein; C474007:Bax protein (53-86); D004268:DNA-Binding Proteins; C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D009842:Oligopeptides; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011987:Receptors, Steroid; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein