title: Nitric oxide regulates lung carcinoma cell anoikis through inhibition of ubiquitin-proteasomal degradation of caveolin-1.
abstract: Anoikis, a detachment-induced apoptosis, is a principal mechanism of inhibition of tumor cell metastasis. Tumor cells can acquire anoikis resistance which is frequently observed in metastatic lung cancer. This phenomenon becomes an important obstacle of efficient cancer therapy. Recently, signaling mediators such as caveolin-1 (Cav-1) and nitric oxide (NO) have garnered attention in metastasis research; however, their role and the underlying mechanisms of metastasis regulation are largely unknown. Using human lung carcinoma H460 cells, we show that NO impairs the apoptotic function of the cells after detachment. The NO donors sodium nitroprusside and diethylenetriamine NONOate inhibit detachment-induced apoptosis, whereas the NO inhibitors aminoguanidine and 2-(4-carboxyphenyl) tetramethylimidazoline-1-oxyl-3-oxide promote this effect. Resistance to anoikis in H460 cells is mediated by Cav-1, which is significantly down-regulated after cell detachment through a non-transcriptional mechanism involving ubiquitin-proteasomal degradation. NO inhibits this down-regulation by interfering with Cav-1 ubiquitination through a process that involves protein S-nitrosylation, which prevents its proteasomal degradation and induction of anoikis by cell detachment. These findings indicate a novel pathway for NO regulation of Cav-1, which could be a key mechanism of anoikis resistance in tumor cells.
authors.affiliation: Department of Physiology, Chulalongkorn University, Bangkok 10330, Thailand. Electronic address: pithi_chan@yahoo.com.
authors.forename: Pithi
authors.initials: P
authors.lastname: Chanvorachote
authors.affiliation: Pharmaceutical Technology (International) Program, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Ubonthip
authors.initials: U
authors.lastname: Nimmannit
authors.affiliation: Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia 26506.
authors.forename: Yongju
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia 26506; Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506.
authors.forename: Siera
authors.initials: S
authors.lastname: Talbott
authors.affiliation: Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506.
authors.forename: Bing-Hua
authors.initials: BH
authors.lastname: Jiang
authors.affiliation: Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia 26506; Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506. Electronic address: yrojan@hsc.wvu.edu.
authors.forename: Yon
authors.initials: Y
authors.lastname: Rojanasakul
mesh_terms: D000818:Animals; D023102:Anoikis / Q000502:physiology*; D051242:Caveolin 1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D003497:Cyclic N-Oxides / Q000378:metabolism; D016166:Free Radical Scavengers / Q000378:metabolism; D006146:Guanidines / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D009362:Neoplasm Metastasis; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000378:metabolism; D009603:Nitroso Compounds / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D051242:Caveolin 1; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D006146:Guanidines; D007093:Imidazoles; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D025801:Ubiquitin; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D009599:Nitroprusside; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D046988:Proteasome Endopeptidase Complex; C004479:pimagedine
references.citation: Carcinogenesis. 2000 Feb;21(2):281-7
references.pmid: 10657969
references.citation: Oncogene. 2000 Jul 6;19(29):3256-65
references.pmid: 10918582
references.citation: J Biol Chem. 2006 Nov 10;281(45):34124-34
references.pmid: 16980304
references.citation: Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1381-5
references.pmid: 7877987
references.citation: Glia. 1999 Jul;27(1):39-52
references.pmid: 10401631
references.citation: Mol Cell Biol. 2003 Apr;23(7):2407-14
references.pmid: 12640124
references.citation: Mol Biol Cell. 2001 Aug;12(8):2229-44
references.pmid: 11514613
references.citation: FEBS Lett. 1998 May 29;428(3):205-11
references.pmid: 9654135
references.citation: Br J Cancer. 1998 Aug;78(4):534-41
references.pmid: 9716040
references.citation: Free Radic Biol Med. 2003 Dec 1;35(11):1457-68
references.pmid: 14642394
references.citation: FEBS Lett. 2005 Nov 7;579(27):6115-20
references.pmid: 16242127
references.citation: Cell. 1992 Feb 21;68(4):673-82
references.pmid: 1739974
references.citation: Jpn J Cancer Res. 1997 Dec;88(12):1190-8
references.pmid: 9473737
references.citation: J Biol Chem. 2004 Jun 4;279(23):24745-56
references.pmid: 15044451
references.citation: Cancer. 1994 Sep 1;74(5):1546-51
references.pmid: 8062187
references.citation: Biochem Soc Trans. 2001 Aug;29(Pt 4):494-9
references.pmid: 11498016
references.citation: Oncogene. 1999 Mar 11;18(10):1881-90
references.pmid: 10086342
references.citation: Cell Death Differ. 1999 Oct;6(10):964-8
references.pmid: 10556973
references.citation: Br J Cancer. 1995 Jul;72(1):41-4
references.pmid: 7541238
references.citation: Nitric Oxide. 2008 Sep;19(2):146-51
references.pmid: 18474261
references.citation: Oncogene. 2005 Feb 17;24(8):1338-47
references.pmid: 15592498
references.citation: J Biol Chem. 2008 Feb 8;283(6):3077-3087
references.pmid: 18029351
references.citation: Oncogene. 2002 Apr 4;21(15):2365-75
references.pmid: 11948420
references.citation: Free Radic Biol Med. 2003 May 1;34(9):1136-45
references.pmid: 12706494
references.citation: Int J Cancer. 2003 Dec 10;107(5):729-38
references.pmid: 14566822
references.citation: J Cell Biol. 1989 Jun;108(6):2401-8
references.pmid: 2472406
references.citation: Br J Cancer. 1998 Jul;78(2):233-9
references.pmid: 9683299
references.citation: J Biol Chem. 2005 Dec 23;280(51):42044-50
references.pmid: 16246840
references.citation: Biochem Biophys Res Commun. 1999 Sep 7;262(3):744-51
references.pmid: 10471396
references.citation: Am J Physiol Cell Physiol. 2005 Mar;288(3):C494-506
references.pmid: 15692148
references.citation: Cancer Res. 2006 Jun 15;66(12):6353-60
references.pmid: 16778213
references.citation: Cancer Res. 1998 Jan 15;58(2):334-41
references.pmid: 9443414
references.citation: Biochem Biophys Res Commun. 1997 Nov 17;240(2):419-24
references.pmid: 9388494
references.citation: Biochem Biophys Res Commun. 1999 Feb 24;255(3):580-6
references.pmid: 10049753
references.citation: Cancer Metastasis Rev. 1998-1999;17(4):439-42
references.pmid: 10453288
references.citation: Nat Rev Mol Cell Biol. 2005 Feb;6(2):150-66
references.pmid: 15688001
references.citation: Nitric Oxide. 2004 Feb;10(1):1-10
references.pmid: 15050529
references.citation: Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):131-5
references.pmid: 8552590
references.citation: Med Res Rev. 2007 May;27(3):317-52
references.pmid: 16991100
references.citation: Oncogene. 1998 Mar;16(11):1391-7
references.pmid: 9525738
references.citation: Am J Physiol Heart Circ Physiol. 2007 Feb;292(2):H893-903
references.pmid: 17012359
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Cancer Res. 1995 Feb 15;55(4):727-30
references.pmid: 7531613
references.citation: Proc Natl Acad Sci U S A. 1995 May 9;92(10):4392-6
references.pmid: 7538668
references.citation: Clin Cancer Res. 1998 Aug;4(8):1873-80
references.pmid: 9717814
references.citation: Life Sci. 2004 Oct 8;75(21):2559-72
references.pmid: 15363661
references.citation: J Biol Chem. 1997 Dec 5;272(49):31138-48
references.pmid: 9388267
references.citation: EMBO J. 1998 Nov 16;17(22):6633-48
references.pmid: 9822607
references.citation: Lancet Oncol. 2001 Mar;2(3):149-56
references.pmid: 11902565
references.citation: Mol Cell Biol. 2000 Mar;20(5):1507-14
references.pmid: 10669728
references.citation: Carcinogenesis. 2002 Jun;23(6):929-41
references.pmid: 12082014
references.citation: Am J Pathol. 2002 Nov;161(5):1647-56
references.pmid: 12414512
references.citation: Mol Cell Biol. 2003 Dec;23(24):9389-404
references.pmid: 14645548
references.citation: Cancer Res. 2001 Jun 1;61(11):4386-92
references.pmid: 11389065
references.citation: Annu Rev Biochem. 1998;67:425-79
references.pmid: 9759494