Nitric oxide regulates lung carcinoma cell anoikis through inhibition of ubiquitin-proteasomal degradation of caveolin-1.
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.
Chanvorachote
Pithi
P
Department of Physiology, Chulalongkorn University, Bangkok 10330, Thailand. Electronic address: pithi_chan@yahoo.com.
Nimmannit
Ubonthip
U
Pharmaceutical Technology (International) Program, Chulalongkorn University, Bangkok 10330, Thailand.
Lu
Yongju
Y
Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia 26506.
Talbott
Siera
S
Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia 26506; Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506.
Jiang
Bing-Hua
BH
Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506.
Rojanasakul
Yon
Y
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.
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*
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
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