Depletion of Endogenous Nitric Oxide Enhances Cisplatin-induced Apoptosis in a p53-dependent Manner in Melanoma Cell Lines

The expression of inducible nitric-oxide synthase in melanoma tumor cells was recently shown to correlate strongly with poor patient survival after combination biochemotherapy (p < 0.001). Furthermore, evidence suggests that nitric oxide, a reaction product of nitricoxide synthase, exhibits antiapoptotic activity in melanoma cells. We therefore hypothesized that nitric oxide antagonizes chemotherapy-induced apoptosis. Whether nitric oxide is capable of regulating cell growth and apoptotic responses to cisplatin treatment in melanoma cell lines was evaluated. We demonstrate herein that depletion of endogenously produced nitric oxide can inhibit melanoma proliferation and promote apoptosis. Moreover, our data indicate that the depletion of nitric oxide leads to changes in cell cycle regulation and enhances cisplatin-induced apoptosis in melanoma cells. Strikingly, we observed that the depletion of nitric oxide inhibits cisplatin-induced wild type p53 accumulation and p21Waf1/Cip1/Sdi1 expression in melanoma cells. When cisplatin-induced p53 binding to the p21Waf1/Cip1/Sdi1 promoter was examined, it was found that nitric oxide depletion significantly reduced the presence of p53-DNA complexes after cisplatin treatment. Furthermore, dominant negative inhibition of p53 activity enhanced cisplatin-induced apoptosis. Together, these data strongly suggest that endogenously produced nitric oxide is required for cisplatin-induced p53 activation and p21Waf1/Cip1/Sdi1 expression, which can regulate melanoma sensitivity to cisplatin. The expression of inducible nitric-oxide synthase in melanoma tumor cells was recently shown to correlate strongly with poor patient survival after combination biochemotherapy (p < 0.001). Furthermore, evidence suggests that nitric oxide, a reaction product of nitricoxide synthase, exhibits antiapoptotic activity in melanoma cells. We therefore hypothesized that nitric oxide antagonizes chemotherapy-induced apoptosis. Whether nitric oxide is capable of regulating cell growth and apoptotic responses to cisplatin treatment in melanoma cell lines was evaluated. We demonstrate herein that depletion of endogenously produced nitric oxide can inhibit melanoma proliferation and promote apoptosis. Moreover, our data indicate that the depletion of nitric oxide leads to changes in cell cycle regulation and enhances cisplatin-induced apoptosis in melanoma cells. Strikingly, we observed that the depletion of nitric oxide inhibits cisplatin-induced wild type p53 accumulation and p21Waf1/Cip1/Sdi1 expression in melanoma cells. When cisplatin-induced p53 binding to the p21Waf1/Cip1/Sdi1 promoter was examined, it was found that nitric oxide depletion significantly reduced the presence of p53-DNA complexes after cisplatin treatment. Furthermore, dominant negative inhibition of p53 activity enhanced cisplatin-induced apoptosis. Together, these data strongly suggest that endogenously produced nitric oxide is required for cisplatin-induced p53 activation and p21Waf1/Cip1/Sdi1 expression, which can regulate melanoma sensitivity to cisplatin. Melanoma is the deadliest form of skin cancer and exhibits extremely aggressive growth characteristics. The prognosis for patients with disseminated disease is invariably very poor. Melanoma is highly resistant to chemotherapy and radiation therapy, and therapies for melanoma have generally been ineffective at best and rarely result in sustained responses. Resistance of cancer to therapy is attributable in part to mechanisms such as altered drug uptake or transport, intracellular detoxification, altered DNA repair, and the dysregulation of the apoptotic pathway (1.Satyamoorthy K. Bogenrieder T. Herlyn M. Trends Mol. Med. 2001; 7: 191-194Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). The tumor suppressor p53 is a sensor of diverse cellular stresses including DNA damage, oxidative stress, and hypoxia, and helps to direct cell cycle arrest and apoptosis at least in part through transcriptional activation of target genes like p21Waf1/Cip1/Sdi1 (p21), 1The abbreviations used are: p21, p21Waf1/Cip1/Sdi1; NO, nitric oxide; NOS, nitric-oxide synthase; eNOS, endothelial NOS; iNOS, inducible NOS; nNOS, neuronal NOS; c-PTIO, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; SIN-1, 3-morpholinosydnonimine; DETA, (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate; ODQ, 1H-(1,2,4)oxadiazole[4,3-a]quinoxalin-1-one; TUNEL,terminal deoxynucleotide transferase-mediated dUTP-fluorescein isothiocyanate nick end labeling; PI, propidium iodide; PBS-T, phosphate-buffered saline + 0.1% Tween 20; l-NMMA, NG-monomethyl-l-arginine; AMG, aminoguanidine; 1400W, N-(3-(aminomethyl)benzyl)acetamidine dihydrochloride; PARP, poly(ADP-ribose) polymerase; DMEM, Dulbecco's modified Eagle's medium; PBS, phosphate-buffered saline; siRNA, small interfering RNA. GADD45α, 14-3-3, and bax (2.Bargonetti J. Manfredi J.J. Curr. Opin. Oncol. 2002; 14: 86-91Crossref PubMed Scopus (311) Google Scholar). Not surprisingly, p53 is the most commonly mutated gene in a broad spectrum of cancers, and its inactivation is frequently associated with tumor progression, resistance to therapy, and poor prognosis. However, the p53 gene is rarely mutated in melanoma (3.Chin L. Merlino G. DePinho R.A. Genes Dev. 1998; 12: 3467-3481Crossref PubMed Scopus (162) Google Scholar), and increased expression is associated with tumor progression (4.Basset-Seguin N. Moles J.P. Mils V. Dereure O. Guilhou J.J. J. Investig. Dermatol. 1994; 103: S102-S106Abstract Full Text PDF PubMed Scopus (77) Google Scholar). Results from several studies suggest that the p53 pathway is dysregulated in melanoma cells, which in turn may lead to inactivation or alteration of p53 function (5.Satyamoorthy K. Chehab N.H. Waterman M.J. Lien M.C. El Deiry W.S. Herlyn M. Halazonetis T.D. Cell Growth & Differ. 2000; 11: 467-474PubMed Google Scholar). For instance, many human melanoma cell lines containing wild type p53 showed abnormalities in the p53 pathway in response to γ-irradiation (6.Bae I. Smith M.L. Sheikh M.S. Zhan Q.M. Scudiero D.A. Friend S.H. O'Connor P.M. Fornace Jr, A.J. Cancer Res. 1996; 56: 840-847PubMed Google Scholar). In recent years, studies have suggested that the retention of wild type p53 may actually confer resistance to therapy in a number of tumor systems (7.McGill G. Fisher D.E. J. Clin. Investig. 1999; 104: 223-225Crossref PubMed Scopus (36) Google Scholar). However, the role of p53 function in melanoma remains unclear. Activated p53 can bind to p53-responsive elements in the promoter of the potent cell-cycle regulator p21 and induce its expression (8.El-Deiry W.S. Tokino T. Velculescu V.E. Levy D.B. Parsons R. Trent J.M. Lin D. Mercer W.E. Kinzler K.W. Vogelstein B. Cell. 1993; 75: 817-825Abstract Full Text PDF PubMed Scopus (7933) Google Scholar). When sufficiently expressed, p21 induces G1 arrest by direct binding of cyclin-dependent kinases (9.Harper J.W. Adami G.R. Wei N. Keyomarsi K. Elledge S.J. Cell. 1993; 75: 805-816Abstract Full Text PDF PubMed Scopus (5235) Google Scholar). Expression of p21 has been implicated as a survival mechanism against therapy (10.Roninson I.B. Cancer Lett. 2002; 179: 1-14Crossref PubMed Scopus (373) Google Scholar). For instance, inhibition of p21 by antisense technology sensitized glioblastoma cells to chemotherapeutic agents (11.Ruan S.B. Okcu M.F. Pong R.C. Andreeff M. Levin V. Hsieh J.T. Zhang W. Clin. Cancer Res. 1999; 5: 197-202PubMed Google Scholar) and to radiation therapy (12.Kokunai T. Urui S. Tomita H. Tamaki N. J. Neurooncol. 2001; 51: 111-119Crossref PubMed Scopus (25) Google Scholar). p21 also appears to protect human colon carcinoma cells and prostate cancer cells against apoptosis (13.Mahyar-Roemer M. Roemer K. Oncogene. 2001; 20: 3387-3398Crossref PubMed Scopus (156) Google Scholar, 14.Martinez L.A. Yang J. Vazquez E.S. del Carmen Rodriguez-Vargas M. Olive M. Hsieh J.-T. Logothetis C.J. Navone N.M. Carcinogenesis. 2002; 23: 1289-1296Crossref PubMed Scopus (67) Google Scholar). Additionally, there is evidence that p21 may protect against p53-mediated apoptosis in human melanoma cells (15.Gorospe M. Cirielli C. Wang X.T. Seth P. Capogrossi M.C. Holbrook N.J. Oncogene. 1997; 14: 929-935Crossref PubMed Scopus (292) Google Scholar). The precise involvement of p21 in the resistance of melanoma to therapy remains largely undefined. Nitric oxide (NO) has recently been implicated in the regulation of p53. Specifically, treating cells with in and changes and of p53 S. P. H. 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J. 1994; 56: PubMed Scopus Google Scholar), and from was from G. was from was from was from for p53 and from The for p21 was from The poly(ADP-ribose) was from The for was from Cell p53 dominant negative and from was from was from Dulbecco's modified Eagle's Dulbecco's phosphate-buffered saline and from Cell and melanoma cell lines from and melanoma cell lines from I. J. and D. G. Cell lines in with and at with generally in at a the of Cell was by the Cell cells by for by the of and at for in accumulation of cells in the was from as D.A. S. 2002; PubMed Scopus Google Scholar). the was in reduced with a of and through a is as a from the uptake was as D.B. 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J. 1999; PubMed Scopus Google Scholar). cells by and with The was the in a containing 0.1% and with and for with was by The by at at for and with a containing and with the to the a with for with DNA and by at at for to the of the p21 promoter was by with the (8.El-Deiry W.S. Tokino T. Velculescu V.E. Levy D.B. Parsons R. Trent J.M. Lin D. Mercer W.E. Kinzler K.W. Vogelstein B. Cell. 1993; 75: 817-825Abstract Full Text PDF PubMed Scopus (7933) Google Scholar). The to form the which was with and a to the The DNA binding reaction was with of in a containing of and of in of for at after which of was and was for at complexes a and by of p53 by of a Expression of melanoma cells was to the cells to in with and to cell of at the of and to for and for to the of the with and with The was for after which the cells with for was by against The of Melanoma Cell has been implicated in increased melanoma progression and we endogenously produced enhanced the proliferation of melanoma cells. The and the used to in the cells after which uptake was depletion in a in proliferation The of lead to in uptake of cells with a in that of enhances cell lead to inhibition of observed in melanoma cells In to iNOS, the presence of also with poor in melanoma patients S. J. M. Clin. Cancer Res. 2000; Google Scholar). increased enhances melanoma cells with SIN-1, which and at a and was and form which is for at a treatment of to cell was also to the inhibition of proliferation by depletion growth inhibition after cisplatin we cells with to the of cisplatin uptake in a after cisplatin treatment. When cells with cisplatin and c-PTIO, proliferation that which was by cisplatin or cisplatin treatment and The of a with cell growth to which that the was to the of of in Melanoma that the of depletion was of cell the and depletion result in a in the of cells or number of cells, that the observed in uptake was a result of cell and of cells with cisplatin in a in a in apoptotic cell of cells with by cisplatin treatment to a in which depletion was of cisplatin-induced DNA that the observed in apoptosis was also in and melanoma cells, these cell lines showed increased apoptosis after depletion activation and of apoptosis T. S.H. J. 1996; PubMed Scopus Google Scholar). which leads to its and by The data indicate that cisplatin treatment activation or depletion with cisplatin treatment in activation and of was with that depletion enhanced cisplatin-induced apoptosis in melanoma cells, a of J.W. 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Res. 1998; 12: PubMed Scopus Google Scholar), to cisplatin treatment also enhanced cisplatin-induced apoptosis The of of to cisplatin treatment the of apoptosis. in Cell and Cell to cycle by showed that treatment with cisplatin to G1 arrest in melanoma cells, through the of depletion to accumulation of cells in the which is with the observed in treatment of cells to a of G1 arrest and accumulation of cells in and the of and cells found the in cells to cisplatin was found in cell cycle observed in and cells. the of depletion and cisplatin treatment the cell cycle in melanoma cells, cell cycle of cells with and cisplatin was a of of cells in the which is generally with cell depletion to increased accumulation of cells in the after which cell cycle was in a sustained in apoptosis after depletion was with cisplatin accumulation of melanoma cells at the for at which cell cycle to to apoptosis can observed after treatment of cells to a of cells in G1 and a of cells in and in these cells was after and increased cell cycle of p53 and p21 p53 pathway can by agents and is in the of cell cycle and DNA Oncogene. 1999; PubMed Scopus Google Scholar). melanoma cells increased cisplatin-induced apoptosis and in cell cycle a role for p53 and p53-responsive cell cycle regulator p21 in the regulation of melanoma cell response to cisplatin. expression of p53 and p21 found to in and melanoma cells. treatment in and accumulation of wild type p53 Expression of the p53 target p21 was also that p53 activity as a result of cisplatin treatment. cisplatin-induced p53 melanoma cell lines with or to cisplatin treatment in with the for and in of cell showed that depletion in a of cisplatin-induced p53 accumulation in melanoma cell lines depletion strongly cisplatin-induced p21 expression in with p53 which suggests that p21 expression is p53 in melanoma cells. depletion p53 or the of increased p53 accumulation p21 expression with depletion or to inhibit cisplatin-induced expression of p53 and p21, that the observed is to found and melanoma cell lines that regulation of cisplatin-induced p53 activation and p21 expression is cells with was to inhibit cisplatin-induced p53 and p21 expression, which is with the was used as the Moreover, with the l-NMMA, the AMG, or the N-(3-(aminomethyl)benzyl)acetamidine to cisplatin treatment also reduced p53 and p21 expression, to a of melanoma cells with which to cisplatin treatment to inhibition of cisplatin-induced p53 accumulation and p21 expression the data strongly suggest that depletion inhibits p53 accumulation and p21 expression in response to cisplatin and enhances cisplatin-induced apoptosis. of p21 p21 can by and we cisplatin-induced p21 expression is p53 The DNA binding activity of p53 after cisplatin treatment was by with a to the of the p21 promoter as the was found to induce DNA binding of p53 to the that increased p21 expression is in melanoma cells. When was to cisplatin the of p53-DNA was p53 DNA and a inhibit cisplatin-induced p53 DNA In a to bind p53 or with binding of the p21 is a ODQ, of was to melanoma cells to cisplatin treatment. with inhibit cisplatin-induced p21 treatment to p53 accumulation and p21 the of the reduced p21 expression and a role for in the of p21 the p53 and cell cycle or the of cisplatin-induced apoptosis these data strongly suggest that p21 expression is and of p53 by the Expression of p53 in Melanoma the increased sensitivity to cisplatin-induced cell in cells was by the inhibition of p53 melanoma cells with a dominant negative form of p53 to wild type p53 Expression of enhanced cisplatin-induced apoptosis by of apoptosis by with The which is with can in cells, in cells is in in type p53 is in and cells after cisplatin treatment. However, p21 expression in cells was reduced to cells, that p53 function is of p53 also reduced p53 expression after cisplatin treatment. However, the of p53 was to cisplatin-induced apoptosis has been shown to in diverse in cellular and is to in the of In we that the depletion of endogenously in melanoma cell lines containing wild type p53 cell enhances cisplatin-induced and inhibits p53 accumulation and the of p21 by cisplatin. Moreover, we showed that the in cisplatin-induced apoptosis in melanoma cells is by regulation of p53 expression, which exhibits a role against cisplatin treatment. with the that patients with significantly survival In the that is and activity is increased in melanoma suggest a role for M. J. Melanoma Res. 1996; PubMed Scopus Google Scholar, D. I. L. M. L. M. J. 2001; PubMed Scopus Google Scholar). of the the role of in the regulation of of to in of is generally that of of may growth in W. M. M. Cell Res. 2002; 12: PubMed Scopus Google and R. 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J. 1997; PubMed Scopus Google Scholar). data that p53 and p21 in melanoma in response to DNA by which suggests that melanoma cells to by cell cycle arrest and DNA repair, cell of a dominant negative form of p53 melanoma cells in a in cisplatin sensitivity as as a of p21 expression after cisplatin that p53 activation to cisplatin melanoma cells from apoptosis. of p53 by reduced cisplatin-induced p53 and p21 expression, which was to apoptosis after cisplatin treatment. of mutated p53 melanoma cells has a dominant which is the in with may of wild type and capable of to DNA we observed that p53 cells p21, at a our data we a for the mechanism of melanoma resistance to cisplatin treatment In is a in the activation of p21 expression after cisplatin-induced DNA Expression of p21 in a of cellular response cell cycle DNA repair, and cell and from apoptosis. of p21 can result in the of G1 cell cycle and can lead to the of apoptosis. the regulation of its expression by the p53 pathway may of in melanoma resistance to In the of p53 to induce p21 tumor cells against several to target for therapies against containing wild type p53. We B. and J. for We also G. D. and for in

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