Insulin-like growth factor 1 receptor antibody induces rhabdomyosarcoma cell death via a process involving AKT and Bcl-x(L).
Insulin-like growth factors (IGFs) and their receptor, IGF-1 receptor (IGF1R), have important roles in growth, development, stress response, aging and cancer. There are many agents that inhibit IGF1R in oncology clinical development, and in some cases, they have been associated with rapid tumor regression. However, it is not clear by which process these targeted agents induce cancer cell death and how to predict such tumor responses. Here, we showed that IGF1R antibody led to rapid cell death and tumor regression in some rhabdomyosarcoma (RMS) cells. Mechanistic analysis revealed a rapid onset of mitochondrial-dependent apoptosis, including mitochondrial depolarization, cytochrome C release and the activation of specific caspases. The antibody sensitive cells had greater dependence on AKT for maintaining downstream signaling and the expression of a constitutively active AKT, which restored AKT-signaling in these cells, inhibited anti-IGF1R induced cell death. Further analysis showed IGF1R antibody-induced hypophosphorylation of BAD and activation of downstream BAX. Interestingly, the examination of RMS cell lines and tumors revealed an inverse correlation between elevated IGF1R and Bcl-2 level (P=0.033), with the sensitive cells lacking Bcl-2 expression. The overexpression of BAD specific target, Bcl-x(L), conferred resistance, whereas Bcl-x(L) knockdown sensitized cells lacking Bcl-2 to anti-IGF1R-induced cell death. We propose that RMS pathogenesis involves increased IGF1R expression that enhances AKT and Bcl-x(L)-mediated cell survival, and the blockage of IGF1R results in inhibition of survival signal from Bcl-x(L) and cell death in the sensitive Bcl-2 negative cells.
Mayeenuddin
L H
LH
Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4265, USA.
Yu
Y
Y
Kang
Z
Z
Helman
L J
LJ
Cao
L
L
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D017526:Receptor, IGF Type 1 / Q000032:analysis / Q000502:physiology*; D012208:Rhabdomyosarcoma / Q000473:pathology / Q000628:therapy*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000502:physiology*
D000906:Antibodies; C494819:BAD protein, human; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt
Cell. 1996 Nov 15;87(4):619-28
8929531
Clin Cancer Res. 2005 Apr 15;11(8):3065-74
15837762
Clin Cancer Res. 2005 Mar 1;11(5):2063-73
15756033
Biochim Biophys Acta. 2006 Aug;1766(1):1-22
16844299
Int J Cancer. 2005 Jan 10;113(2):316-28
15386423
Dev Cell. 2002 Nov;3(5):631-43
12431371
J Immunol. 1992 Jul 15;149(2):535-40
1624800
Cancer Res. 2007 Jan 15;67(2):756-64
17234787
Cancer Res. 2003 Feb 1;63(3):627-35
12566306
Am J Transplant. 2007 Sep;7(9):2082-9
17614980
Cytokine Growth Factor Rev. 2006 Aug;17(4):305-23
16621671
J Immunol. 1997 Aug 1;159(3):1225-32
9233617
J Clin Oncol. 2009 Dec 1;27(34):5800-7
19786654
Nat Protoc. 2007;2(11):2719-27
18007607
Clin Cancer Res. 2007 Oct 1;13(19):5834-40
17908976
Oncogene. 2007 Feb 26;26(9):1324-37
17322918
Nat Rev Drug Discov. 2005 Dec;4(12):988-1004
16341064
Nat Rev Drug Discov. 2007 Oct;6(10):821-33
17906644
Mol Cell. 2000 Sep;6(3):683-92
11030347
Endocrinology. 1997 Mar;138(3):1355-8
9048647
Brain Res Dev Brain Res. 2004 Sep 17;152(2):255-63
15351513
Nature. 1999 Jun 3;399(6735):483-7
10365962
Mol Cancer Ther. 2005 Aug;4(8):1214-21
16093437
Cell. 1995 Jan 27;80(2):285-91
7834748
Nat Protoc. 2006;1(5):2315-9
17406473
Cancer Res. 2008 Oct 1;68(19):8039-48
18829562
Cell. 2007 Jun 29;129(7):1261-74
17604717
Mol Cell Biol. 1999 Oct;19(10):7203-15
10490655
Annu Rev Biochem. 2004;73:87-106
15189137
Cell. 1997 Dec 26;91(7):961-71
9428519
Oncogene. 2009 Aug 27;28(34):3009-21
19581933
Cell. 1996 Mar 22;84(6):889-97
8601312
Cancer Res. 2003 Dec 15;63(24):8912-21
14695208