Inhibition of insulin-like growth factor II (IGF-II)-dependent cell growth by multidentate pentamannosyl 6-phosphate-based ligands targeting the mannose 6-phosphate/IGF-II receptor.
The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) binds M6P-capped ligands and IGF-II at different binding sites within the ectodomain and mediates ligand internalization and trafficking to the lysosome. Multivalent M6P-based ligands can cross-bridge the M6P/IGF2R, which increases the rate of receptor internalization, permitting IGF-II binding as a passenger ligand and subsequent trafficking to the lysosome, where the IGF-II is degraded. This unique feature of the receptor may be exploited to design novel therapeutic agents against IGF-II-dependent cancers that will lead to decreased bioavailable IGF-II within the tumor microenvironment. We have designed a panel of M6P-based ligands that bind to the M6P/IGF2R with high affinity in a bivalent manner and cause decreased cell viability. We present evidence that our ligands bind through the M6P-binding sites of the receptor and facilitate internalization and degradation of IGF-II from conditioned medium to mediate this cellular response. To our knowledge, this is the first panel of synthetic bivalent ligands for the M6P/IGF2R that can take advantage of the ligand-receptor interactions of the M6P/IGF2R to provide proof-of-principle evidence for the feasibility of novel chemotherapeutic agents that decrease IGF-II-dependent growth of cancer cells.
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Megan E
ME
Zavorka
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Christopher M
CM
Connelly
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Rosslyn
R
Grosely
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Richard G
RG
MacDonald
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D008024:Ligands; D008247:Lysosomes / Q000378:metabolism; D008360:Mannosephosphates / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D055503:Protein Multimerization / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D017527:Receptor, IGF Type 2 / Q000378:metabolism*
D000970:Antineoplastic Agents; C035170:IGF2 protein, human; D008024:Ligands; D008360:Mannosephosphates; D017527:Receptor, IGF Type 2; D007335:Insulin-Like Growth Factor II
apoptosis; biochemistry; insulin-like growth factors; receptor
Bioorg Med Chem Lett. 2008 May 15;18(10 ):3085-9
18068981
Curr Med Chem. 2007;14(28):2945-53
18220730
Proc Natl Acad Sci U S A. 2016 May 17;113(20):E2766-75
27140600
Cancer Metastasis Rev. 1998-1999;17(4):383-90
10453282
Exp Cell Res. 2009 Nov 15;315(19):3301-11
19769965
Cancer Res. 1999 Nov 15;59(22):5692-4
10582686
J Biol Chem. 1993 Oct 25;268(30):22338-46
8226743
J Biol Chem. 2004 Sep 10;279(37):38658-67
15252023
J Cell Biol. 1987 Jun;104(6):1735-42
2953746
J Biol Chem. 1986 Jul 15;261(20):9090-3
3013875
Mol Cancer Ther. 2007 Feb;6(2):607-17
17308058
J Biol Chem. 2009 Dec 11;284(50):35215-26
19840944
J Biol Chem. 2000 Jun 23;275(25):18647-56
10764761
J Biol Chem. 1989 May 15;264(14):7962-9
2542254
J Biol Chem. 1988 Feb 15;263(5):2563-70
2963004
J Biol Chem. 1994 Oct 28;269(43):26944-52
7929433
Cell. 2001 Aug 24;106(4):395-8
11525725
J Biol Chem. 1985 Aug 5;260(16):9435-42
2991246
Annu Rev Cell Biol. 1989;5:483-525
2557062
Genes Cells. 2008 Sep;13(9):977-86
18691225
Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20926-31
18087038
Biochemistry. 2007 Nov 6;46(44):12604-17
17927214
Hum Mol Genet. 2014 Jan 1;23(1):117-28
23962719
J Biol Chem. 1999 Dec 24;274(52):36905-11
10601243
FEBS J. 2012 Aug;279(15):2695-713
22681933
Breast Cancer Res Treat. 1998 Feb;47(3):219-33
9516078
Carbohydr Res. 2001 May 18;332(2):183-9
11434376
Nat Genet. 2001 Feb;27(2):153-4
11175780
Cytokine Growth Factor Rev. 2008 Apr;19(2):111-20
18308616
J Biol Chem. 1999 Oct 15;274(42):29889-96
10514470
EMBO J. 2002 Mar 1;21(5):1054-62
11867533
J Immunol Methods. 1986 May 22;89(2):271-7
3486233
Dev Biol. 1996 Aug 1;177(2):517-35
8806828
Development. 1993 Jul;118(3):731-6
8076514
FEBS J. 2009 Apr;276(7):1915-29
19236480
Bioorg Med Chem. 1997 Jan;5(1):21-40
9043655
FASEB J. 1997 Jan;11(1):60-7
9034167
Front Biosci. 2002 May 01;7:e214-22
11991830
Bioessays. 2001 Apr;23(4):333-43
11268039
J Biol Chem. 2009 Dec 11;284(50):35201-14
19801653
J Biol Chem. 2002 Dec 6;277(49):47205-12
12374794
Liver. 2001 Oct;21(5):320-8
11589768
Cancer Res. 2004 Sep 1;64(17):6058-64
15342387
Biochim Biophys Acta. 2009 Apr;1793(4):605-14
19046998
Mol Reprod Dev. 2008 Nov;75(11):1678-87
18361416
Cell. 1993 Oct 8;75(1):73-82
8402902
Exp Cell Res. 2001 Apr 1;264(2):388-96
11262195
Hepatology. 2014 Dec;60(6):1942-56
24753158
Biochem Soc Trans. 1990 Jun;18(3):367-74
2164980
Cancer Res. 2005 Dec 15;65(24):11236-40
16357124
Hepatology. 2008 Jul;48(1):146-56
18537183
J Biol Chem. 1980 Dec 25;255(24):11942-8
6254987
Br J Cancer. 2014 Jun 10;110(12):2855-64
24853186
Biochim Biophys Acta. 2002 Sep 19;1572(2-3):317-40
12223278
Mol Endocrinol. 1998 Nov;12(11):1661-72
9817593
Oncogene. 2004 Dec 16;23(58):9359-68
15543235
J Biol Chem. 1991 Nov 15;266(32):21687-92
1657978
J Biol Chem. 1999 Jan 8;274(2):1164-71
9873065
Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8392-6
7690960
Biochem Biophys Res Commun. 1988 May 16;152(3):1248-54
2454100
Nat Rev Mol Cell Biol. 2003 Mar;4(3):202-12
12612639
Proc Natl Acad Sci U S A. 1979 Sep;76(9):4322-6
291966
Org Lett. 2004 Dec 23;6(26):4921-4
15606100
J Biol Chem. 2001 Jun 29;276(26):23986-91
11297550
Endocrinology. 2002 Nov;143(11):4287-94
12399424
J Biol Chem. 2000 Jun 23;275(25):18638-46
10764735
Bioorg Med Chem Lett. 2008 Dec 1;18(23):6240-3
18929485
Cancer Res. 2006 Feb 15;66(4):1940-8
16488992
Endocrinology. 1999 Jun;140(6):2928-31
10342887
J Biol Chem. 1988 Feb 15;263(5):2553-62
2963003
Glycobiology. 2015 Jun;25(6):591-606
25573276
Biosci Rep. 2006 Feb;26(1):7-17
16779663
J Control Release. 2011 Oct 30;155(2):326-30
21763370
Oncogene. 2003 Aug 21;22(35):5436-45
12934103
Nature. 1987 Sep 24-30;329(6137):301-7
2957598
J Biol Chem. 2004 Aug 6;279(32):34000-9
15169779
Curr Opin Struct Biol. 2009 Oct;19(5):534-42
19801188
Am J Pathol. 2003 Jan;162(1):321-8
12507915
J Biol Chem. 2009 Sep 25;284(39):26591-602
19638343
Mol Endocrinol. 1996 Jun;10(6):642-51
8776724
J Biol Chem. 1999 Aug 20;274(34):24408-16
10446221
Biomed Res Int. 2015;2015:538019
25866791
Front Endocrinol (Lausanne). 2014 Dec 23;5:224
25566194
J Biol Chem. 1998 Aug 28;273(35):22358-66
9712856
Endocrinology. 1992 Sep;131(3):1359-68
1380441