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© 2007 American Society for Nutrition J. Nutr. 137:1591S-1596S, June 2007

Supplement: Aromatic Amino Acids and Related Substances: Chemistry, Biology, Medicine, and Application: SESSION 4

Specific Amino Acid Dependency Regulates the Cellular Behavior of Melanoma1–3,

Ya-Min Fu and Gary G. Meadows*

Cancer Prevention and Research Center, Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, WA 99164-6713

* To whom correspondence should be addressed. E-mail: meadows{at}wsu.edu.


   ABSTRACT
TOP
 ABSTRACT
LITERATURE CITED
 
Relative specific amino acid dependency is one of the metabolic abnormalities of melanoma cells and metabolic studies of this dependency are in their infancy. Herein, we review the current studies in this area and present new information that adds to the understanding of how tyrosine (Tyr) and phenylalanine (Phe) dependency as well as other amino acids regulate the cell behaviors of melanoma cells. Amino acid dependency of human melanoma cells is multifactorial and restricting Tyr and Phe to melanoma triggers a series of alterations in metabolic and signaling pathways in a time-ordered fashion to alter different cellular behaviors. For example, at early time points, the reduction of Tyr and Phe alters metabolic reactions quantitatively or qualitatively. The alterations include modulation of integrin/focal adhesion kinase (FAK)/G protein pathways and the plasminogen activator (PA)/PA inhibitor pathways to inhibit tumor cell invasion. At later time periods, a further drop in intracellular amino acids induces more metabolic alterations to impact the FAK/Ras/Raf and Bcl-2 pathways leading to apoptosis. The threshold effects and the targeting of multiple pathways by restriction of specific amino acids provide a connection between the metabolic alterations and signaling pathways that modulate the cellular behaviors of melanoma cells. Decoding the metabolic alterations that connect amino acid concentration to the crucial step(s) in signaling is important and an exciting area of cancer research.

Malignant melanoma continues to increase in incidence in the United States (1) and metastasis is the major cause of death in melanoma patients. The process of metastasis is very complicated and includes invasion of melanoma cells to adjacent tissues, intravasation and transport through the circulatory system, arrest of the cells at a secondary site, extravasation from the circulatory system, and growth of the invaded cells in the secondary organ. All free amino acids are essential metabolic substrates for tumor cells. Interestingly, melanoma cells as well as other solid tumors exhibit relative specific amino acid dependency that functionally regulates their survival, proliferation, and metastasis. For example, human A375 and murine B16 melanoma cells are tyrosine (Tyr)4/phenylalanine (Phe)-dependent. Deprivation of these amino acids inhibits growth and survival of these melanoma cells without significantly affecting normal cells (2–8). Moreover, Tyr/Phe restriction also inhibits invasion and metastasis of melanoma as well as other cancers (4,5,9).

Metabolism is the basis for all cellular behavior. Specific amino acid dependency is one of the metabolic abnormalities of cancer cells and can also be regarded as the metabolic basis for their malignant behavior. In other words, the malignant behaviors of melanoma cells could be dependent on or related to their dependency on specific amino acids. However, the relative specific amino acid dependency of cancers has not been properly studied and most of the studies are descriptive. Thus, the mechanism by which specific amino acid restriction targets the metabolic abnormalities to inhibit the malignant behavior(s) of melanoma is largely unknown.

Specific amino acid dependency modulates invasion-related signaling/function proteins

Invasion through the extracellular matrix (ECM) by melanoma cells is important to their ability to invade normal tissues and metastasize. Invasion involves a 3-step process, including: 1) attachment and detachment of the tumor cells to ECM constituents; 2) secretion of proteolytic enzymes to degrade the local matrix; and 3) migration of the tumor cells into the area of matrix altered by proteolysis. Our previous studies showed that specific amino acid restriction affects all 3 steps by modulating a number of related molecules in various melanoma cell lines and this, in general, is consistent with the findings that restriction of Tyr/Phe or methionine (Met) in A375 melanoma cells and of Tyr/Phe, Met, or glutamine (Gln) in MeWo cell inhibits invasion [(5); Y-M. Fu and G. G. Meadows, unpublished data] (Table 1).


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  		TABLE 1 Effects of amino acid deprivation on invasion and invasion-related proteins and signaling molecules in melanoma. The following is an overview of previously published findings regarding the effects of amino acid deprivation on human A375 and MeWo melanoma and murine B16BL6 melanoma

 
Melanoma cells attach to the cell surface via integrins that bind to ECM proteins like fibronectin and laminin. Integrins also interact via their cytoplasmic domains to components of the actin cytoskeleton and signaling molecules within the cell (10). Thus, integrins have important roles in cell motility, invasiveness, and survival of melanoma cells (11–15). Focal adhesion kinase (FAK) is a major mediator of integrin signaling and a key regulator of focal adhesion dynamics and cell movement (16–20). Also, FAK is constitutively active in human malignant melanoma and related to its aggressive behavior (21). We found that specific amino acid restriction modulates the integrin/FAK pathway and the actin cytoskeleton remodeling of melanoma cells (8). The integrin/FAK pathway activates small GTPases (G proteins) such as Ras, Rho, Rac, and Cdc42 (22), which direct cell movement and regulate actin cytoskeletal arrangement (23–27). In A375 melanoma, Rho activation is required for motility of A375 melanoma (28). We examined the effects of specific amino acid restriction on the GTP-binding activity of these G proteins (Fig. 1). Restriction of Tyr/Phe or Met in A375 melanoma cells and of Tyr/Phe, Met, or Gln in MeWo melanoma cells inhibits invasion and the inhibition of GTP binding to Ras and Rho in A375 cells and that of Rho in MeWo cells. This is consistent with the inhibition of invasion by restriction of these specific amino acids. These data indicate that specific amino acid restriction inhibits invasion via inhibition of the Ras/Rho pathway. Additionally, Ras and Rho signaling also influences the binding of integrins to their ligands that are the components of the ECM, such as laminin and fibronectin (12,29). This binding also controls the activation of integrins (30).


Figure 1
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  		FIGURE 1  Specific amino acid restriction differentially modulates activity of G proteins. A375 and MeWo melanoma cells were cultured in complete or specific amino acid-free minimum essential medium (MEM) (Gibco BRL Life Technologies) for 3 d. The GTP-binding activity of each G protein was analyzed using specific Ras, Rho, Rac-1, and Cdc42 signal transduction assay kits from Cytoskeleton according to the manufacturer's instructions. The amounts of activated G proteins were determined by immunoblot analysis with the antibodies contained in the kits, as previously described (6,8). An equal amount of protein from cells grown under complete or amino acid-restricted culture conditions were used in each assay to identify the relative GTP-binding activity of each G protein. Lane C, Lysates from cells cultured in complete medium; lane T/P, lysates from cells cultured in Tyr/Phe-free medium; lane Met, lysates from cells cultured in Met-free medium; lane Gln, lysates from cell cultured in Gln-free medium. The relative activity of each G protein in cells cultured in amino acid-free medium is expressed as a ratio compared with control cells cultured in complete medium (numbers at the bottom of the blot). The blot is representative of 3 separate experiments with similar results.

 
Another integrin-mediated migration pathway is the FAK/CT10 sarcoma oncogene cellular homolog (Crk)/Crk-associated substrate (Cas)/Rac pathway. In this pathway, the focal contact proteins, p130Cas and paxillin, are phosphorylated by FAK. Then the SH2/SH3 domain adapter protein, Crk, binds to Cas or paxillin. The paxillin/Crk or Cas/Crk complexes control cell migration via Rac-GTPase. However, the results in Figure 1 along with previous findings (5,8) indicate that molecules like paxillin and Rac1 do not play a major role in controlling invasion of A375 and MeWo melanoma cells during specific amino acid restriction, and alterations in these proteins are not consistent with the inhibition of invasion. GTP binding activity of Cdc42 protein is reduced by Tyr/Phe restriction in MeWo cells (Fig. 1). This could indicate that inhibition of Cdc42, Ras, and Rho activity are all important in mediating inhibition of invasion in MeWo cells during Tyr/Phe restriction. In general, we conclude that specific amino acid restriction modulates the integrin/FAK/G protein pathways and the urokinase-type plasminogen activator (PA)/tissue-type PA (tPA)/PA inhibitor (PAI) pathways to inhibit invasion of melanoma cells. However, the current findings do not explain the differences in specific amino acid dependency in regulation of invasion among different melanoma cell lines. Thus, additional studies are required to examine the involvement of specific Ras- and Rho-related binding partners.

Specific amino acid restriction induces mitochondria-initiated apoptosis of melanoma

Selective restriction of various specific amino acids causes apoptosis of melanoma cells and it is a relatively slow process (3,6,31) in which modulation of cell survival pathways are involved. Melanoma cells are adhesion-dependent cells. FAK is required for cell survival in adhesion-dependent cells, and phosphorylation of specific Tyr sites in the molecule is needed to perform this function (32–34). Although the inhibition of phosphorylation of FAK by specific amino acid restriction is consistent with induction of apoptosis in melanoma cells (6,8), alteration of FAK itself does not explain the whole process of apoptosis induced by specific amino acid restriction.

In this regard, we examined the downstream events of FAK, including modulation of the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway and the Bcl-2 family proteins. Raf is a central component of the Ras/Raf/ MAPK pathway and is an important regulator of apoptosis (31,35–40). The phosphorylation on serine338 and Tyr441 of Raf is required for its activation (41–43). The anti-apoptotic or pro-apoptotic function of Raf primarily depends on its interaction with the Bcl-2 family proteins at the mitochondrial membrane (35,39,44). FAK regulates the proapoptotic function of Bax, a member of the Bcl-2 family of proteins (33,34,45).

Raf-1, through its N-terminal homology domain, binds to and interacts with the Bcl-2 family of proteins. Interaction between the Raf-1 and the Bcl-2 family of proteins affects the function of these proteins to control apoptosis. For example, the interaction of Raf-1 and Bcl-2 at the outer mitochondrial membrane enables Raf-1 to phosphorylate Bad, another member of the Bcl-2 family of proteins, and inactivate its pro-apoptotic function. This would also activate the anti-apoptotic function of Bcl-2 (35,38,39,44,46). Thus, the phosphorylation status of Bcl-2-related proteins and their subcellular distribution along with the subcellular distribution of Raf-1 regulate apoptosis (35,38,39,46,47). Raf-1 phosphorylation and distribution are modulated by specific amino acid restriction in A375 cells. Met restriction almost completely inhibits phosphorylated Raf in A375 cells (Fig. 2). Tyr/Phe restriction increases the amount of Bax protein and its mitochondrial localization and stimulates the cleavage of Bid and translocation into mitochondria in A375 cells [Fig. 3; (3)]. Meanwhile, the pro-apoptotic death-associated protein 3 (DAP3), which does not belong to the Bcl-2 family, is decreased in A375 melanoma, indicating that it is not involved in induction of apoptosis. Based on these results, we conclude that specific amino acid restriction interferes with the FAK/Ras/Raf survival pathways through modulation of the interaction between Raf and the Bcl-2 protein family during induction of apoptosis. However, specific amino acid restriction differentially regulates these pathways between A375 and MeWo melanoma cells, indicating that all melanoma cells do not utilize the same signaling pathways.


Figure 2
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  		FIGURE 2  Specific amino acid restriction differentially regulates the Raf/ERK pathway in A375 and MeWo. Melanoma cells were cultured in complete or amino acid-free MEM. The phosphorylation of Raf, ERK, and p38 MAPK was analyzed by immunoblot, as previously described (6,8). The phospho-specific antibodies Akt were obtained from Cell Signaling Technology. Lane C, Lysate from cells grown in complete medium. Lanes 1d–4d, Cells cultured from 1 to 4 d, respectively, in Tyr/Phe (T/P)-, Gln-, or Met-deprived medium. The relative phosphorylation of each protein in cells cultured in amino acid-free medium is expressed as a ratio to cells cultured in complete medium (numbers at the bottom of blot). The blot is representative of 3 separate experiments with similar results.

 

Figure 3
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  		FIGURE 3  Immunoblot analysis of DAP3, Bax, and Bcl-2. The antibody for DAP3 was obtained from Cell Signaling Technology, the antibody for Bax protein was obtained from Trevigen, and the antibody for Bcl-2 protein was obtained from DAKO. The immunoblot analysis was conducted as previously described (6,8). Lane C, Lysate from cells cultured in complete medium. Lanes 1d–4d, Cells cultured from 1 to 4 d, respectively, in Tyr/Phe (T/P)-, Gln-, or Met-deprived medium. The relative amount of each protein in each lane is expressed as a percentage of control cells (numbers at bottom of the blot). The blot is representative of 3 separate experiments with similar results.

 
The mitochondria are major metabolic organelles that generate ATP to provide energy and they contain enzymes and/or functional proteins that regulate apoptosis. Apoptosis induced by specific amino acid restriction is metabolism related. This slower apoptotic pathway also depends on the alteration of mitochondrial integrity and function. Because specific amino acid restriction modulates Bcl-2 family members that play important roles in maintaining mitochondrial integrity and in progression of human melanoma (31,48,49), we conducted additional experiments to examine the alterations in mitochondrial integrity and function of melanoma cells under specific amino acid restrictions. Loss in mitochondrial integrity leads to the release of cytochrome c that can lead to caspase-dependent cell death, and the release of apoptosis-inducing factor that can lead to caspase-independent cell death (31,50–52). We previously showed that Tyr/Phe deprivation modulates mitochondrial transmembrane potential and that this modulation leads to leakage of cytochrome c from the mitochondria into the cytosol of A375 melanoma and activation of caspases (3).

In addition to changes in mitochondrial integrity, we also found that other mitochondrial functions are affected by Tyr/Phe, Met, and Gln restriction. Energy production (ATP synthesis) is decreased (Fig. 4). ATP content is maximally decreased 2 d after deprivation of Tyr/Phe and Met; however, maximal depletion is not achieved by Gln deprivation until d 3.


Figure 4
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  		FIGURE 4  Specific amino acid restriction reduces the amount of ATP in A375 melanoma. Cells were cultured in complete or amino acid-free medium. For measurement of ATP, cells were suspended in 85 mmol/L perchloric acid and centrifuged to precipitate protein. The supernatant (0.05 mL) was added to 0.45 mL of 50 mmol/L HEPES (pH 7.8). Then, 0.1 mL of the sample was added into a 96-well FluoroNunc (white) plate (Nunc) followed by the addition of 0.1 mL of commercial luciferin-luciferase kit (Sigma Chemical). Chemiluminescence was measured on a CytoFluor 4000 plate reader (Applied Biosystems) at the various time periods. Values are means ± SD of triplicate samples. *Gln different from Met and T/P at P < 0.05 by the Tukey test after ANOVA. The plot is representative of 2 separate experiments with similar results.

 
Intracellular reactive oxygen species participate in a diverse array of biological processes, including cell growth, apoptosis, and cellular senescence. Cancer and transformed cells produce elevated levels of reactive oxygen species and major sources of these species are found in the mitochondria. Generation of reactive oxygen species is increased by Tyr/Phe, Met, and Gln restriction in A375 melanoma (Y-M. Fu and G. G. Meadows, unpublished data); however, Gln restriction did not induce apoptosis in these cells. Moreover, because ATP levels also decrease in response to Gln, this further suggests that generation of reactive oxygen species and inhibition of ATP production do not correlate with apoptosis in A375 melanoma cells.

Amino acid restriction changes metabolism in the mitochondria; however, the exact relation between the alterations in metabolism and the induction of apoptosis is still not completely known. For example, it is possible that apoptosis-inducing factor, a mitochondrial flavin-adenine dinucleotide-binding oxidoreductase associated with oxidative phosphorylation, could play a critical role in mediating apoptosis due to specific amino acid restriction (51–53) and this remains a target for further exploration.

Specific amino acid dependency: multifactorial and threshold effects

In malignant cells, different mutant cellular proteins cause aberrant interactions in signaling systems and metabolic pathways to maintain their malignant behaviors. Thus, metabolic and signaling pathways are key regulators of cellular behaviors. Recent studies indicate that some enzymatic defects of melanoma might be the cause for arginine dependency (54–56) in addition to the Tyr/Phe dependency of melanomas. However, to date, studies on melanoma metabolism do not indicate the metabolic pathways or reactions that are linked directly to specific amino acid dependency-regulated cellular behavior.

Restriction of any amino acid is a metabolic stress to melanoma cells. This stress affects metabolism and cell signaling to modulate cellular behavior. Then why is melanoma relatively dependant on certain amino acids? The simple answers are: 1) the stress level induced by restriction of specific amino acids is different in each individual melanoma cell line; and 2) the level or degree of stress between melanoma and normal cells is different for each amino acid restriction. These statements are supported by previous studies that reveal the threshold effects of different amino acid restrictions on melanoma and other solid tumors (5,6,9,54,57–62).

The cell surface amino acid transporters in human hepatoma and melanoma cells are not damaged by restriction of selective amino acids (62,63). The proximal event for melanoma cells during restriction is the gradual reduction in intracellular amino acid levels (62). Usually, the appearance of biological effects induced by amino acid restriction follow a time-ordered sequence: 1) inhibition of invasion; 2) inhibition of growth; and 3) induction of apoptosis. The sequence is reversed when amino acid levels are restored (5,6,54,57–62). This indicates that the thresholds for each intracellular amino acid to maintain different cellular behaviors in melanoma are different. For example, during Tyr/Phe restriction, the intracellular levels of Tyr in A375 cells are higher at 24 and 48 h when inhibition of invasion and growth occur than at 72 h when apoptosis is prevalent (5,6,62). Because metabolism is the basis of cellular behaviors, these results indicate that there are differences in the metabolic demands on cells to maintain these different behaviors. The metabolic demand of the tumor cell for Tyr that is required to maintain its invasive characteristics and proliferative capacity are higher than the demand for Tyr to protect the cell from death. Thus, the threshold effects of 1 amino acid restriction in modulating multiple cellular behaviors are linked to the intracellular specific amino acid levels that trigger a series of alterations in metabolic and signaling pathways in a time-ordered fashion to alter different cellular behaviors. At a particular point, the reduction of certain amino acids alters metabolic reactions quantitatively or qualitatively. The cellular metabolism cannot support the need for a particular cellular behavior. Moreover, the metabolic perturbations induce a series of alterations in signaling pathways to inhibit this behavior.

We also found that the intracellular levels of Tyr and Phe in A375 cells are considerably higher than those found in a normal human fibroblast cell line and that the levels in fibroblasts do not decrease during restriction of these amino acids nor do they undergo apoptosis in response to Tyr/Phe restriction (6,62). This indicates that the threshold effect associated with restriction of these amino acids is different between melanoma cells and normal cell lines because their metabolic thresholds for cell survival are different.

The threshold effects and multiple pathways targeting restriction of amino acids provide an important connection between metabolic alterations and signaling pathways in modulation of the cellular behaviors of melanoma cells. The diagram in Figure 5 depicts a scheme that integrates the current understanding of this relation. Metabolic studies on specific amino acid dependency of melanoma are in their infancy. It is still unknown which metabolic alterations connect to the signaling pathways that control cell behaviors. Moreover, it is not currently possible to predict the relative specificity of amino acid dependency of different melanomas due to their heterogeneity. However, the multifactorial effects of specific amino acid restriction on melanoma cells would be an advantage in the treatment independent from the heterogeneity of the melanoma, because restriction: 1) inhibits invasion (4,5,8,9); 2) inhibits proliferation (6,7,9,54–56,64); 3) induces apoptosis (6,9,54–56); and 4) enhances the effect of chemotherapy (65–71). The investigations in this field could lead to the development of novel metabolic approaches to control melanoma.


Figure 5
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  		FIGURE 5  Diagram of the multiple pathway-targeting and threshold effects of specific amino acid restriction on cell invasion and cell survival. Depicted is a scheme indicating that there are thresholds associated with the concentration of a specific amino acid that modulates invasion and survival of tumor cells. The decrease in amino acid concentration most likely results in metabolic changes that selectively modulate various signaling proteins and pathways that lead to inhibition of invasion and initiation of apoptosis.

 

   FOOTNOTES
 
1 Published in a supplement to The Journal of Nutrition. Presented at the "Conference on Aromatic Amino Acids and Related Substances: Chemistry, Biology, Medicine, and Application" held July 20–21, 2006 in Vancouver, Canada. The conference was sponsored by Ajinomoto Company, Inc. The organizing committee for the symposium and Guest Editors for the supplement were: Katsuji Takai, Dennis M. Bier, Luc Cynober, Sidney M. Morris, Jr., and Yoshiharu Shimomura. Guest Editor disclosure: Expenses to travel to the meeting were paid by Ajinomoto Company, Inc. for K. Takai, D. M. Bier, L. Cynober, S. M. Morris, Jr., and Y. Shimomura; D. M. Bier has consulted for Ajinomoto Company, Inc. on scientific issues. Back

2 Supported by the National Cancer Institute, grant number R01 CA 77604. Back

3 Author disclosures: G. G. Meadows, travel expenses to attend the meeting were paid by the Ajinomoto Company, Inc.; Y-M. Fu, no conflicts of interest. Back

4 Abbreviations used: DAP3, pro-apoptotic death associated protein 3; ECM, extracellular matrix; FAK, focal adhesion kinase; Gln, glutamine; MAPK, mitogen-activated protein kinase; Met, methionine; PA, plasminogen activator, PAI, plasminogen activator inhibitor; Phe, phenylalanine; tPA, tissue-type plasminogen activator; Tyr, tyrosine. Back


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Introduction to the Transdisciplinary International Conference on Aromatic Amino Acids and Related Substances: Chemistry, Biology, Medicine, and Application
J. Nutr., June 1, 2007; 137(6): 1501S - 1503S.
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