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.
Highlights
Cells, endothelial cells, and epithelial cells [5], Cav-1 is greatly reduced in most oncogenically transformed and cancer cells (6 –10)
Nitric Oxide Inhibits Detachment-induced Apoptosis of H460 Cells—nitric oxide (NO) has been shown to play an important role in the regulation of cancer cell metastasis; the underlying mechanism of this regulation is unclear
To test whether NO might regulate this process by inhibiting detachment-induced apoptosis or anoikis, which is a crucial step in the metastasis of cancer cells, we first investigated anoikis of human lung cancer H460 cells in response to various specific NO donors and inhibitors
Summary
Cells, endothelial cells, and epithelial cells [5], Cav-1 is greatly reduced in most oncogenically transformed and cancer cells (6 –10). Previous studies have shown that Cav-1 acts as a negative regulator of anoikis [17, 18], and its elevated expression in lung carcinoma is closely associated with the increased metastasis capacity and poor survival of the patients [19]. Because resistance to anoikis is a key step in metastasis development and because Cav-1 has been implicated in this process, we investigated the potential regulation of Cav-1 by NO and studied its role in anoikis of human lung carcinoma cells. Using molecular and pharmacological approaches, we report here that NO plays an important role in Cav-1 regulation and anoikis function of human lung cancer H460 cells. Our study reveals the existence of a novel mechanism of anoikis regulation, which might be exploited in metastasis and cancer therapy
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