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).
Kolluri
Siva Kumar
SK
Cancer Center, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Zhu
Xiuwen
X
Zhou
Xin
X
Lin
Bingzhen
B
Chen
Ya
Y
Sun
Kai
K
Tian
Xuefei
X
Town
James
J
Cao
Xihua
X
Lin
Feng
F
Zhai
Dayong
D
Kitada
Shinichi
S
Luciano
Frederick
F
O'Donnell
Edmond
E
Cao
Yu
Y
He
Feng
F
Lin
Jialing
J
Reed
John C
JC
Satterthwait
Arnold C
AC
Zhang
Xiao-kun
XK
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