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Activation of Nuclear Factor-B in Human Metastatic Melanoma Cells and the Effect of Oxidative Stress¹

Department of Medicine and the Chao Family Comprehensive Cancer Center, University of California-Irvine, Orange, California 92868

	ABSTRACT

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The biological basis for the general pharmacological resistance of human melanoma is unknown. A unique biochemical feature of the melanocyte is the synthesis of melanin, which leads to the generation of hydrogen peroxide and the consumption of reduced glutathione. This activity produces a state of chronic oxidative stress in these cells. We demonstrated previously that the expression of the c-jun family was dysregulated in metastatic melanoma cells compared with normal human melanocytes (D. T. Yamanishi et al., J. Invest. Dermatol., 97: 349–353, l991). In the current investigation, we measured the levels of two major redox response transcription factors, nuclear factor-B (NF-B) and activator protein-1, in metastatic melanoma cells and normal melanocytes and their response to oxidative stress. The basal DNA-binding activity of NF-B as measured by the electrophoretic mobility shift assay in metastatic melanoma cells was increased 4-fold compared with that of normal melanocytes. This level of binding was paralleled by a 1.5- to 4-fold increase in the expression of p50 (NF-B1), p65 (Rel-A), and IB- as measured by Northern blot analysis. In contrast, the expression of p75 (c-rel) was markedly decreased (60%) in melanoma cells compared with normal melanocytes. Following oxidative stress produced by enzyme-generated H₂O₂, free H₂O₂, or incubation with buthionine sulfoximine, NF-B binding activity increased 1.5- to 2.5-fold in melanoma cells (buthionine sulfoximine > H₂O₂), but only slightly in normal melanocytes. In contrast, activator protein-1 binding activity was unaffected or increased in normal melanocytes in response to oxidative stress, but was either unaffected or decreased in melanoma cells. These results suggest that the redox regulation of melanoma cells at the molecular level is fundamentally different from normal melanocytes and may offer a unique avenue for preventive or therapeutic intervention as well as new insights into the pathogenesis of melanocyte transformation.

	INTRODUCTION

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Human melanoma is almost uniformly resistant to cytotoxic intervention (1) . Although specific mechanisms of drug resistance have been described in selected cell lines (2) , no uniform or unifying concept has emerged to explain the general resistance of melanoma to a wide range of chemotherapeutic agents.

In the past several years the NF-B/Rel³ and AP family of transcription factors have been shown to participate in the control of a diverse range of genes involved in inflammation, immunological responsiveness, development, growth control, and oncogenesis (3, 4, 5, 6) . These two families of transcriptional factors also are redox sensitive (6, 7, 8, 9, 10) . In general, NF-B is activated by prooxidant conditions, whereas AP-1 is stimulated by antioxidants (7 , 8) . The regulation of these two transcription factors is also quite different. NF-B is inactivated in the cytoplasm by inhibitor proteins (IB) that respond to exogenous stimuli (such as oxidative stress) by phosphorylating and releasing active dimeric complex (e.g., p50/p65 and p50/p75) that translocates to the nucleus (11 , 12) . De novo synthesis of the dimers is not required for binding to DNA and gene activation to occur. In contrast, AP-1 activation requires synthesis of its precursor proteins, c-Fos and c-Jun (6) . Transcription factors for both families bind to promoter regions of a large variety of genes (5 , 6) . We previously have shown that the expression of c-jun and related molecules is differentially regulated in melanoma cells compared with normal melanocytes (13) .

One of the unique biochemical features of cells of melanocyte lineage is the synthesis of melanin (14 , 15) . Generation of H₂O₂ occurs at several points in the biochemical pathway; additionally, the synthesis of the phaeomelanin subtype requires a constant supply of cysteine via glutathione (14 , 16) . Both the generation of H₂O₂ and the synthesis of cysteine lowers intracellular reduced glutathione. We previously have shown that melanoma cells are considerably less efficient at handling H₂O₂-induced oxidative stress compared with melanocytes (17) . It is also known that many melanomas have low catalase levels as well as abnormalities of manganese superoxide dismutase (18, 19, 20, 21) . All of these conditions favor a prooxidant intracellular state and activation of redox-sensitive genes, a result that may produce a basis for resistance to exogenous agents (20 , 22) . We therefore measured the levels of NF-B and AP-1 binding activity under basal and oxidative stress conditions in melanoma cells and normal melanocytes as the initial basis for exploration of a drug-resistant phenotype.

	MATERIALS AND METHODS

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Cell Culture.
Two to five human Caucasian neonatal foreskins were placed in 0.25% trypsin at 4°C overnight. The tissues were scraped to recover the melanocytes, pooled, and cultured in MCDB 153 (Sigma, St. Louis, MO) medium containing 2% FCS, 0.3% bovine pituitary extract (Clonetics Corp., San Diego, CA), 10 ng/ml phorbol myristate-13-acetate, 2.0 mM calcium chloride, 5 µg/ml insulin, and 0.1 mM 3-isobutyl-1-methyl-xanthine (Sigma). Each normal melanocyte pool (1W, 9W, 12W, and 11W) contained the total yield of cells from two to five Caucasian neonatal foreskins. Human metastatic melanoma cells (c83-2C, c81-61, and c81-46A) were cultured in F-10 (Fisher Scientific, Pittsburgh, PA) medium containing 5% FCS and 5% newborn calf serum (13) .

Northern Blot Analysis.
Total RNA was isolated by detergent lysis followed by phenol-chloroform extraction and ethanol precipitation. Ten µg of RNA were size fractionated on denaturing formaldehyde agarose gels and transferred to nylon filters by capillary blotting. Blots were exposed to ³²P-labeled cDNA probes and hybridized at 42°C for 2 h, using Rapid-Hyb Buffer (Amersham, Arlington Heights, IL). Autoradiographs were quantified by densitometry, using Molecular Analyst software (Bio-Rad, Emeryville, CA). NF-B1 (p50) RNA expression was detected using a 1.5-kb EcoRI insert, c-Rel (p75) was detected using a 2.34-kb EcoRI insert, Rel A (p65) was detected using a 0.95-kb EcoRI insert, and IB was detected using a 1.190-kb EcoRI insert (23) .

EMSA.
Nuclear proteins were extracted from detergent-lysed cells by dialysis with hypertonic buffer (20 mM HEPES, 3.5 mM NaCl, 1 mM DTT, 1 mM phenylmethylsulfonyl fluoride; Sigma) for 2 h at 10°C. Consistent loading was determined by Coomassie Blue (Sigma) staining of protein after SDS-PAGE. Samples of nuclear protein (5 µg) were incubated with 600,000 cpm of ³²P-labeled consensus oligonucleotides of AP-1 or NF-B (Promega, Madison, WI). Following a 1-h incubation, samples were electrophoresed in a low ionic strength polyacrylamide gel. Quantitation of protein:DNA complexes was accomplished by densitometry as described for Northern analysis.

Western Analysis.
Nuclear proteins were isolated as described above. Five µg of nuclear protein were fractionated by SDS-PAGE and transferred to nitrocellulose membranes. The membranes were blocked in 5% milk in TBST [20 µM Tris-HCl (pH 7.6), 1377 µM NaCl, 0.5% Tween 20], incubated with rabbit polyclonal antibodies to IB- (1:1000 dilution in 3% milk; Ref. 24 ), and then incubated with horseradish peroxidase-linked goat anti-rabbit IgG (Santa Cruz Biotechnology, Santa Cruz, CA). Membranes were washed in TBST between steps. Immune-complexed IB- proteins were detected using SuperSignal enhanced chemiluminescence (Pierce, Rockford, IL).

Oxidative Stress Treatment.
H₂O₂ was quantitated by the oxidation of ferrous iron (Fe⁺²) to ferric iron (Fe⁺³) and reacted with xylene orange, producing a colorimetric change that was detected by absorbance at 560 nm (25) . Glucose (present in all media at 1.0 mg/ml) and glucose oxidase (Boehringer Mannheim, Indianapolis, IN) were used to enzymatically generate H₂O₂ in cells. Exposure for 15 min to 10.0 U/ml glucose oxidase enzyme-generated H₂O₂ was equivalent to 0.012 mM free H₂O₂. Exposure for 1 min to 0.001% free H₂O₂ was equivalent to 0.3 mM H₂O₂. Buthionine sulfoximine (BSO) was preincubated with the cells at a concentration of 10 mM for 24 h. All chemicals were from Sigma.

	RESULTS

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EMSA of NF-B in Normal Human Melanocytes and Melanoma Cells.
The DNA-binding activity of NF-B from three different pools of normal melanocytes and three different metastatic melanoma cell lines under basal culture conditions, as measured by EMSA and quantitated by laser densitometry, is shown in Fig. 1A . The DNA-binding activity of NF-B from melanoma cells, as measured by EMSA, was on average 4-fold higher than the DNA-binding activity of NF-B from normal melanocytes. A representative blot of the DNA-binding activity of NF-B from normal melanocytes and metastatic melanoma cells is shown in Fig. 1B . The DNA-binding activity of NF-B from normal melanocytes and melanoma cells was unaffected by preincubation with cycloheximide (Fig. 2) .

View larger version (34K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. EMSA of NF-B in normal human melanocytes and metastatic melanoma cells. Nuclear proteins were extracted from cultured normal melanocytes or melanoma cells incubated with 32P-labeled consensus oligonucleotides of NF-B for 1 h and electrophoresed. A, laser densitometric quantitation of the protein:DNA complexes. Values for three melanoma lines (c83-2C, c81-61, c81-46A) and four separate pools of melanocytes (9W, 1W, 11W, 12W) are expressed as relative indexes; bars, SD. B, EMSA of normal melanocyte pools 9W and 1W and melanoma cell lines c83-2C, c81-46A, and c81-61.

View larger version (76K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. EMSA of normal melanocyte pool 1W and metastatic melanoma cell line c83-2C following incubation with cycloheximide (10 µg/ml) for 1 h before nuclear extraction at times indicated.

Northern Blot Analysis of p50, p65, p75, and IB- in Normal Human Melanocytes and Melanoma Cells.

View larger version (35K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. Northern blot analysis of p50, p65, p75, and IB- expression by normal human melanocytes and metastatic melanoma cells. A, total RNA was isolated, size fractionated, and transferred to nylon filters. Blots were hybridized to 32P-cDNA probes and quantitated by laser densitometry. Values are expressed as relative indexes; bars, SD. B, Northern blot of normal melanocyte pools 9W and 1W and melanoma cell lines c83-2C, c81-46A, and c81-61.

EMSA of NF-B in Normal Human Melanocytes and Melanoma Cells following Oxidative Stress.

View larger version (38K): [in this window] [in a new window] [Download PPT slide]   Fig. 4. EMSA of NF-B in normal human melanocytes and metastatic melanoma cells following oxidative stress. A, cells were incubated with BSO, free H2O2, or enzyme-generated H2O2 as described in "Materials and Methods." Laser densitometer was used to quantitate the protein:DNA complexes shown in C. B, summary of densitometry data expressed as percentages of control from three melanocyte pools (1W, 9W, 12W) and three melanoma cell lines c83-2C, c81-46A, and c81-61. C, EMSA of normal melanocyte pool 1W and melanoma cell line c81-46A performed as described in legend to Fig. 1 .

View larger version (42K): [in this window] [in a new window] [Download PPT slide]   Fig. 5. EMSA of AP-1 in normal human melanocytes and metastatic melanoma cells following oxidative stress. A, cells were incubated with BSO, free H2O2, or enzyme-generated (glucose oxidase) H2O2 as described in "Materials and Methods." Laser densitometer was used to quantitate the protein:DNA complexes shown in C. B, summary of densitometry data expressed as percentages of control from three normal melanocyte pools (1W, 9W, 12W) and three melanoma cell lines (c83-2C, c81-46A, c81-61). C, EMSA of normal melanocyte pool 9W and melanoma cell line c83-2C; conditions were as for Fig. 1 except a 32P-labeled AP-1 oligonucleotide consensus sequence was used.

Western Analysis of Nuclear IB-.

	DISCUSSION

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Our investigations demonstrate that the transcription factor NF-B is constitutively activated in melanoma cells compared with normal melanocytes and is further increased under conditions of oxidative stress. In contrast, the binding activity of the transcription factor AP-1 was unaffected or decreased in melanoma cells in response to oxidative stress. These results suggest that the expression and redox control mechanisms involving these transcription factors are altered during transformation of the melanocyte to its malignant counterpart. The quantitative levels of AP-1 and NF-B were affected by culture conditions, but the qualitative relationship between levels was preserved, (data not shown); this is important in as much as the growth requirements of normal melanocytes and melanoma cells require different culture additives.

High expression of NF-B and rel-related proteins has been shown in other tumor cell lines, although interpretation has been limited because the normal phenotype has not been studied (26) . The increased expression of p50, p65, and IB- in melanoma cells could be the result of autoregulatory induction by the higher NF-B activity rather than a cause of the increased NF-B binding activity. The basis for increased NF-B binding activity is generally unknown; however, Shattuck-Brandt and Richmond (27) showed recently that in Hs294T melanoma cells, enhanced degradation of IB- contributed to the endogenous activation of NF-B. Our data in two other melanoma lines and in melanocytes indicate that IB- is present in the nuclear protein and is increased by the withdrawal of serum or TPA (Fig. 6) . This suggests that in general, a more complex regulatory mechanism than enhanced degradation of IB- underlies the enhanced NF-B binding activity in melanoma cells.

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Fig. 6. Western analysis of nuclear IB-. Cells were incubated in the presence or absence of TPA (95-1W) or serum (c81-61, c83-2C). Nuclear proteins were isolated and analyzed as described in "Materials and Methods.".

Because many toxic agents, including chemotherapeutic drugs and radiation, generate reactive oxygen species, manipulation of these transcription factors may be useful in effecting a therapeutic outcome (28 , 29) .

The parallel constitutive elevation of NF-B binding activity and p50, p65, and IB- expression as well as the decrease in p75 expression in melanoma cells compared with normal melanocytes may also offer specific targets for small molecule modulation or antisense inhibition, in particular because experiments in other systems suggest specific roles for the NF-B/Rel subunits (28 , 29) . For example, antisense inhibition of Rel A/NF-B activity can block cellular adhesion to the extracellular matrix and inhibit in vivo tumorigenicity in nude mouse models (28) . Whether the imbalance in NF-B/Rel factors in melanoma cells is cause or effect has not been determined by the current study, but exploration of the role of these subunits in oncogenesis of the melanocyte should be informative. Results from this current investigation plus our recent observation that melanoma cells quench reactive oxygen species considerably less effectively than normal melanocytes should also offer unique targets for intervention (16) .

	ACKNOWLEDGMENTS

 
We thank Dr. John Hiscott (Lady Davis Institute for Medical Research, Montreal, Canada) for NF-B/Rel plasmids, Dr. Nancy Rice (NCI, Frederick, MD) for the IB- antibody, and the doctors and nurses at Long Beach Memorial Hospital, Long Beach, CA, for neonatal foreskins (protocol approved by University of California-Irvine and Long Beach Memorial Hospital Institutional Review Boards).

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported in part by grants from the National Institutes of Health (Grant CA62203) and the Waltmar Foundation.

² To whom requests for reprints should be addressed, at Chao Family Comprehensive Cancer Center, UC-Irvine Medical Center, 101 The City Drive, Building 23, Orange, CA 92868. Phone: (714) 456-6310; Fax: (714) 456-2240; E-mail: flmeyske{at}uci.edu

³ The abbreviations used are: NF-B, nuclear factor-B; AP, activator protein; TBST, Tris-buffered saline-Tween [20 µM Tris-HCl (pH 7.6), 1377 µM NaCl, 0.5% Tween 20]; BSO, buthionine sulfoximine; EMSA, electrophoretic mobility shift assay; TPA, phorbol myristate-13-acetate.

⁴ Unpublished data.

Received 8/ 5/98; revised 2/ 1/99; accepted 2/ 3/99.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Meyskens, F. L. Articles by Tohidian, N. B. Search for Related Content PubMed PubMed Citation Articles by Meyskens, F. L., Jr. Articles by Tohidian, N. B.