Survivin enhances motility of melanoma cells by supporting Akt activation and {alpha}5 integrin upregulation.
Survivin expression in melanoma is inversely correlated with patient survival. Transgenic mice harboring melanocyte-specific overexpression of survivin exhibit increased susceptibility to UV-induced melanoma and metastatic progression. To understand the mechanistic basis for metastatic progression, we investigated the effects of survivin on the motility of human melanocytes and melanoma cells. We found that survivin overexpression enhanced migration on fibronectin and invasion through Matrigel, whereas survivin knockdown under subapoptotic conditions blocked migration and invasion. In melanocytes, survivin overexpression activated the Akt and mitogen-activated protein kinase pathways. Akt phosphorylation was required for survivin-enhanced migration and invasion, whereas Erk phosphorylation was required only for enhanced invasion. In both melanocytes and melanoma cells, survivin overexpression was associated with upregulation of α5 integrin (fibronectin receptor component), the antibody-mediated blockade or RNA interference-mediated knockdown of which blocked survivin-enhanced migration. Knockdown of α5 integrin did not affect Akt activation, but inhibition of Akt phosphorylation prevented α5 integrin upregulation elicited by survivin overexpression. Together, our results showed that survivin enhanced the migration and invasion of melanocytic cells and suggested that survivin may promote melanoma metastasis by supporting Akt-dependent upregulation of α5 integrin.
McKenzie
Jodi A
JA
Departments of Dermatology and Oncological Sciences, and the Huntsman Cancer Institute; University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA.
Liu
Tong
T
Goodson
Agnessa G
AG
Grossman
Douglas
D
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D004789:Enzyme Activation; D052816:Foreskin / Q000166:cytology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D039081:Integrin alpha5beta1 / Q000235:genetics*; D008297:Male; D008544:Melanocytes / Q000166:cytology / Q000502:physiology; D008545:Melanoma / Q000473:pathology / Q000503:physiopathology*; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology; D000077022:Survivin; D015854:Up-Regulation
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D039081:Integrin alpha5beta1; D008869:Microtubule-Associated Proteins; D000077022:Survivin; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases
J Biol Chem. 1998 May 1;273(18):11177-82
9556606
Cancer Cell. 2010 Jan 19;17(1):53-64
20129247
Br J Cancer. 1995 Jun;71(6):1243-7
7779718
J Biol Chem. 2000 Aug 11;275(32):24565-74
10835423
Nat Rev Cancer. 2002 Feb;2(2):91-100
12635172
Nat Rev Cancer. 2008 Jan;8(1):61-70
18075512
Int J Cancer. 2009 Aug 1;125(3):585-95
19330838
Cell. 1996 May 31;85(5):683-93
8646777
Clin Exp Metastasis. 2003;20(3):203-13
12741679
Cancer Res. 2007 Jun 1;67(11):5172-8
17545596
Exp Cell Res. 2003 May 15;286(1):128-37
12729801
Cancer Res. 2009 Jun 15;69(12):4954-8
19470765
Am J Pathol. 2009 Apr;174(4):1524-33
19342374
Dig Dis Sci. 2009 Jan;54(1):89-96
18594980
J Clin Oncol. 2003 Jan 15;21(2):306-12
12525523
J Cell Sci. 2002 Oct 1;115(Pt 19):3729-38
12235283
J Cell Sci. 2009 Jan 15;122(Pt 2):199-206
19118212
Br J Dermatol. 2007 Jun;156(6):1204-13
17388918
J Cell Biochem. 2007 Jul 1;101(4):816-29
17243120
Cancer Res. 2005 May 1;65(9):3531-4
15867343
J Invest Dermatol. 1999 Dec;113(6):1076-81
10594755
J Invest Dermatol. 2006 Oct;126(10):2247-56
16728972
Histopathology. 1994 Mar;24(3):249-56
7515372
J Biol Chem. 2001 Aug 24;276(34):32353-61
11418614
Cancer Metastasis Rev. 2005 Jun;24(2):273-85
15986137
J Biol Chem. 2003 Mar 14;278(11):9790-5
12514183
J Clin Invest. 2002 Jan;109(2):285-6
11805141
Cancer Res. 2003 Feb 1;63(3):567-72
12566297
J Clin Invest. 2001 Oct;108(7):981-90
11581299
Int J Dermatol. 2009 Apr;48(4):426-30
19335434
J Invest Dermatol. 2000 Oct;115(4):625-32
10998134
Clin Cancer Res. 2002 Dec;8(12):3728-33
12473582
Nature. 2002 Jun 27;417(6892):949-54
12068308
Science. 2005 Dec 2;310(5753):1499-504
16322459
J Cell Sci. 1999 Aug;112 ( Pt 16):2677-91
10413676
Int J Oncol. 2007 Nov;31(5):1111-7
17912437
Carcinogenesis. 2008 Jan;29(1):194-201
17916908
Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1557-61
1371877
J Clin Invest. 2007 Mar;117(3):719-29
17318262
N Engl J Med. 2006 Jul 6;355(1):51-65
16822996
Nat Rev Cancer. 2009 Aug;9(8):537-49
19629069
FEBS Lett. 2000 Jun 2;474(2-3):201-7
10838085
Exp Mol Med. 2008 Oct 31;40(5):486-94
18985006
Cell. 2000 Jan 7;100(1):57-70
10647931
Oncogene. 2004 Jan 8;23(1):39-48
14712209
Invest Ophthalmol Vis Sci. 2009 Jan;50(1):57-67
18775869
Oncogene. 2006 Nov 2;25(52):6968-74
16702945
Biochem Biophys Res Commun. 2005 Aug 12;333(4):1269-75
15979576
Dev Cell. 2005 Nov;9(5):663-73
16256741
Annu Rev Cell Dev Biol. 2005;21:695-718
16212512
Oncogene. 2010 Feb 25;29(8):1227-37
19946336
Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):635-40
11149963
Int J Cancer. 2005 Dec 20;117(6):1032-8
15986442
J Biol Chem. 2007 Aug 3;282(31):22964-76
17562714
J Invest Dermatol. 2003 Jan;120(1):48-55
12535197