在癌症發展的過程中，癌細胞必須要改變或持續激活代謝路徑上的調控，才能達到足夠的營養供應，滿足癌細胞快速分裂的特性時對於能量上的龐大需求，約略在1950年代，癌症科學家就已經確立麩醯胺酸對於提供癌細胞作為其生長所必須能量的重要性－麩醯胺酸可以作為癌細胞快速分裂時所需之脫氧核糖核酸合成的原料 ; 麩醯胺酸也可促進NADPH的合成，NADPH是脂質的合成中，不可或缺的電子提供者 ; 麩醯胺酸也可以經由電子傳遞鏈產生癌細胞所需ATP及其他非必須胺基酸的合成，幫助構築癌細胞發展所需的大分子產物的合成。此外，也在1950年，科學家們在具有淋巴瘤的老鼠身上，釐清了天門冬氨酸的分解酵素－天門冬氨酸酶，對於有抑制淋巴瘤的效果，並將此發現用於臨床病人身上，在比較有施予天門冬氨酸酶以及沒有施予的急性淋巴白血病的病人之中，結果指出有施予的病人具有較高比例的治癒並回復急性淋巴白血病的病情。除了這兩個胺基酸之外，其他人體中的胺基酸代謝，並沒有在癌症發展的過程中被明確的定位，因此，我們選用了兩個在肝癌以及乳癌的發生過程中扮演重要角色的調節因素－內質網壓力以及雌性激素受體活化，來做為觀察胺基酸代謝在癌症發展過程中的改變，我們選定了胺基酸代謝上的速率決定步驟酵素，或是參與著重要生理意義的合成以及分解的酵素，在我們初步的結果中，我們發現當處理內質網壓力誘導物tunicamycin時，肝癌細胞株：Huh-7中的半胱氨酸及絲氨酸的生合成酵素的mRNA表現量會顯著的上升，同時，精氨酸、組氨酸、脯氨酸、苯丙氨酸及支鏈氨基酸的分解酵素的mRNA，也會在內質網壓力存在下顯著的上升 ; 另一方面，當我們處理雌性激素至乳癌細胞株：MCF-7，活化其雌性激素受體時，我們也可以發現絲氨酸及甲硫氨酸合成酵素有mRNA有顯著上升的情形，同時也伴隨著精氨酸、苯丙氨酸和酪氨酸的分解酵素mRNA上升。除了細胞的實驗外，我們同時也在帶有雌性激素受體病人的乳癌檢體之中驗證了這樣的現象，這樣的結果顯示了當癌細胞處於不同的促進癌細胞生長的環境下，會呈現不同的對於胺基酸代謝及合成的調控，幫助其生長發育 ; 同時，而我們也可以針對這些發生抗的胺基酸代謝做進一步的釐清，找出在不同情形所誘導的癌症發展的過程中有可能作為治療標的胺基酸代謝路徑，有朝一日，能作為日後治療癌症的新策略。

During tumor progression, metabolic switch is required for constitutively activating the uptake and metabolism of nutrients that facilitate cancer cell survival and fuel them growth. Since 1950s cancer biologists have recognized the significance of glutamine (Q) as a tumor nutrients, including nucleotide biosynthesis, which is needed for replicating its genome, NADPH production, which is an indispensable electron donor for lipid synthesis, ATP generation and other nonessential amino acids biosynthesis. Meanwhile, the tumor-inhibitory properties of asparaginase (ASNase) were observed in lymphoma-bearing mice in 1950. Clinical studies have demonstrated that patient with acute lymphoblastic leukemia (ALL) treated with ASNase have higher recovery efficiency than ALL patients did not treat with this drug. Except for the two amino acids, the roles of the other amino acids are not fully elucidated in cancer progression. For that reason, we want to clarify whether the expression of amino acid metabolic genes is altered in different carcinogenic progress such as endoplasmic reticulum (ER) stress, hormone receptor activation, overexpression/activation of Her2/Neu and further to define the relationship between them. According to the bioinformatics wedsites survey, We choose genes that participate in rate-limiting steps and/or play biological significances of amino acid metabolism (ana- or/and cata-bolic). We found that the genes of cysteine biosynthesis were predominantly elevated, and catabolic genes of arginine, histidine, proline, phenylalanine and branched-chain amino acids (BCAAs) were upregulated in ER stress-treated Huh-7 hepatocellular carcinoma cells.On the other hand, expression of anabolic genes of serine and methionine were upregulated and catabolic genes of arginine, phenylalanine and tyrosine metabolism were significantly increased when estrogen receptor-positive MCF-7 breast cancer cells were treated with estrogen. Consistent with our in vitro studies, estrogen receptor-positive clinical breast cancer patient specimens show the same expression pattern of anabolic genes of serine and methionine and catabolic genes of arginine, phenylalanine and tyrosine metabolism. These results suggested that amino acid metabolisms are reprogrammed in the different context of cancer, and we will focus on the influence of this altered amino acid metabolisms during cancer progression in detail and try to find potential candidates for cancer therapy in the future.

Abcouwer, S.F., Marjon, P.L., Loper, R.K., and Vander Jagt, D.L. (2002). Response of VEGF expression to amino acid deprivation and inducers of endoplasmic reticulum stress. Invest Ophthalmol Vis Sci 43, 2791-2798.
Alo, P.L., Visca, P., Marci, A., Mangoni, A., Botti, C., and Di Tondo, U. (1996). Expression of fatty acid synthase (FAS) as a predictor of recurrence in stage I breast carcinoma patients. Cancer 77, 474-482.
Altucci, L., Addeo, R., Cicatiello, L., Dauvois, S., Parker, M.G., Truss, M., Beato, M., Sica, V., Bresciani, F., and Weisz, A. (1996). 17beta-Estradiol induces cyclin D1 gene transcription, p36D1-p34cdk4 complex activation and p105Rb phosphorylation during mitogenic stimulation of G(1)-arrested human breast cancer cells. Oncogene 12, 2315-2324.
Arinze, I.J., and Patel, M.S. (1973). Inhibition by phenylpyruvate of gluconeogenesis in the isolated perfused rat liver. Biochemistry 12, 4473-4479.
Bandyopadhyay, S., Pai, S.K., Watabe, M., Gross, S.C., Hirota, S., Hosobe, S., Tsukada, T., Miura, K., Saito, K., Markwell, S.J., et al. (2005). FAS expression inversely correlates with PTEN level in prostate cancer and a PI 3-kinase inhibitor synergizes with FAS siRNA to induce apoptosis. Oncogene 24, 5389-5395.
Barbosa-Tessmann, I.P., Chen, C., Zhong, C., Schuster, S.M., Nick, H.S., and Kilberg, M.S. (1999). Activation of the unfolded protein response pathway induces human asparagine synthetase gene expression. J Biol Chem 274, 31139-31144.
Bauer, D.E., Hatzivassiliou, G., Zhao, F., Andreadis, C., and Thompson, C.B. (2005). ATP citrate lyase is an important component of cell growth and transformation. Oncogene 24, 6314-6322.
Bennegard, K., Lindmark, L., Eden, E., Svaninger, G., and Lundholm, K. (1984). Flux of amino acids across the leg in weight-losing cancer patients. Cancer Res 44, 386-393.
Block, T.M., Mehta, A.S., Fimmel, C.J., and Jordan, R. (2003). Molecular viral oncology of hepatocellular carcinoma. Oncogene 22, 5093-5107.
Bos, C., Gaudichon, C., and Tome, D. (2002). Isotopic studies of protein and amino acid requirements. Curr Opin Clin Nutr Metab Care 5, 55-61.
Breckenridge, D.G., Germain, M., Mathai, J.P., Nguyen, M., and Shore, G.C. (2003). Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 22, 8608-8618.
Brodsky, J.L., Werner, E.D., Dubas, M.E., Goeckeler, J.L., Kruse, K.B., and McCracken, A.A. (1999). The requirement for molecular chaperones during endoplasmic reticulum-associated protein degradation demonstrates that protein export and import are mechanistically distinct. J Biol Chem 274, 3453-3460.
Brusselmans, K., De Schrijver, E., Verhoeven, G., and Swinnen, J.V. (2005). RNA interference-mediated silencing of the acetyl-CoA-carboxylase-alpha gene induces growth inhibition and apoptosis of prostate cancer cells. Cancer Res 65, 6719-6725.
Bundred, N., and Howell, A. (2002). Fulvestrant (Faslodex): current status in the therapy of breast cancer. Expert Rev Anticancer Ther 2, 151-160.
Calfon, M., Zeng, H., Urano, F., Till, J.H., Hubbard, S.R., Harding, H.P., Clark, S.G., and Ron, D. (2002). IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415, 92-96.
Campbell, J.S., Hughes, S.D., Gilbertson, D.G., Palmer, T.E., Holdren, M.S., Haran, A.C., Odell, M.M., Bauer, R.L., Ren, H.P., Haugen, H.S., et al. (2005). Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc Natl Acad Sci U S A 102, 3389-3394.
Cascino, A., Muscaritoli, M., Cangiano, C., Conversano, L., Laviano, A., Ariemma, S., Meguid, M.M., and Rossi Fanelli, F. (1995). Plasma amino acid imbalance in patients with lung and breast cancer. Anticancer Res 15, 507-510.
Cauley, J.A., Lucas, F.L., Kuller, L.H., Stone, K., Browner, W., and Cummings, S.R. (1999). Elevated serum estradiol and testosterone concentrations are associated with a high risk for breast cancer. Study of Osteoporotic Fractures Research Group. Ann Intern Med 130, 270-277.
Chajes, V., Cambot, M., Moreau, K., Lenoir, G.M., and Joulin, V. (2006). Acetyl-CoA carboxylase alpha is essential to breast cancer cell survival. Cancer Res 66, 5287-5294.
Chalbos, D., Chambon, M., Ailhaud, G., and Rochefort, H. (1987). Fatty acid synthetase and its mRNA are induced by progestins in breast cancer cells. J Biol Chem 262, 9923-9926.
Chang, S.M., Kuhn, J.G., Robins, H.I., Schold, S.C., Spence, A.M., Berger, M.S., Mehta, M.P., Bozik, M.E., Pollack, I., Schiff, D., et al. (1999). Phase II study of phenylacetate in patients with recurrent malignant glioma: a North American Brain Tumor Consortium report. J Clin Oncol 17, 984-990.
Chen, C.J., Yang, H.I., Su, J., Jen, C.L., You, S.L., Lu, S.N., Huang, G.T., and Iloeje, U.H. (2006). Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. Jama 295, 65-73.
Chen, E.I., Hewel, J., Krueger, J.S., Tiraby, C., Weber, M.R., Kralli, A., Becker, K., Yates, J.R., 3rd, and Felding-Habermann, B. (2007). Adaptation of energy metabolism in breast cancer brain metastases. Cancer Res 67, 1472-1486.
Ching, N., Grossi, C., Jham, G., Angers, J., Zurawinsky, H., Ching, C.Y., and Nealon, T.F., Jr. (1984). Plasma amino acid and serum unesterified fatty acid deficits and the effect of nutritional support in chemotherapy treatment. Surgery 95, 730-738.
Clarke, E.F., Lewis, A.M., and Waterhouse, C. (1978). Peripheral amino acid levels in patients with cancer. Cancer 42, 2909-2913.
Colgan, S.M., Hashimi, A.A., and Austin, R.C. (2011). Endoplasmic reticulum stress and lipid dysregulation. Expert Rev Mol Med 13, e4.
Corraliza, I., and Moncada, S. (2002). Increased expression of arginase II in patients with different forms of arthritis. Implications of the regulation of nitric oxide. J Rheumatol 29, 2261-2265.
Costello, L.C., and Franklin, R.B. (2005). 'Why do tumour cells glycolyse?': from glycolysis through citrate to lipogenesis. Mol Cell Biochem 280, 1-8.
Costello, L.C., and Franklin, R.B. (2006). Tumor cell metabolism: the marriage of molecular genetics and proteomics with cellular intermediary metabolism; proceed with caution! Mol Cancer 5, 59.
Dang, C.V., Le, A., and Gao, P. (2009). MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res 15, 6479-6483.
Dang, C.V., and Semenza, G.L. (1999). Oncogenic alterations of metabolism. Trends Biochem Sci 24, 68-72.
DeBerardinis, R.J., and Cheng, T. (2010). Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29, 313-324.
DeBerardinis, R.J., Lum, J.J., Hatzivassiliou, G., and Thompson, C.B. (2008). The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7, 11-20.
DeBerardinis, R.J., Mancuso, A., Daikhin, E., Nissim, I., Yudkoff, M., Wehrli, S., and Thompson, C.B. (2007). Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A 104, 19345-19350.
Desbois-Mouthon, C., Baron, A., Blivet-Van Eggelpoel, M.J., Fartoux, L., Venot, C., Bladt, F., Housset, C., and Rosmorduc, O. (2009). Insulin-like growth factor-1 receptor inhibition induces a resistance mechanism via the epidermal growth factor receptor/HER3/AKT signaling pathway: rational basis for cotargeting insulin-like growth factor-1 receptor and epidermal growth factor receptor in hepatocellular carcinoma. Clin Cancer Res 15, 5445-5456.
Diehn, M., Cho, R.W., Lobo, N.A., Kalisky, T., Dorie, M.J., Kulp, A.N., Qian, D., Lam, J.S., Ailles, L.E., Wong, M., et al. (2009). Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458, 780-783.
Dubik, D., and Shiu, R.P. (1988). Transcriptional regulation of c-myc oncogene expression by estrogen in hormone-responsive human breast cancer cells. J Biol Chem 263, 12705-12708.
Dumitrescu, R.G., and Cotarla, I. (2005). Understanding breast cancer risk -- where do we stand in 2005? J Cell Mol Med 9, 208-221.
Eidne, K.A., Flanagan, C.A., Harris, N.S., and Millar, R.P. (1987). Gonadotropin-releasing hormone (GnRH)-binding sites in human breast cancer cell lines and inhibitory effects of GnRH antagonists. J Clin Endocrinol Metab 64, 425-432.
Elstrom, R.L., Bauer, D.E., Buzzai, M., Karnauskas, R., Harris, M.H., Plas, D.R., Zhuang, H., Cinalli, R.M., Alavi, A., Rudin, C.M., et al. (2004). Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 64, 3892-3899.
Farazi, P.A., Glickman, J., Horner, J., and Depinho, R.A. (2006). Cooperative interactions of p53 mutation, telomere dysfunction, and chronic liver damage in hepatocellular carcinoma progression. Cancer Res 66, 4766-4773.
Fernandez, P.M., Tabbara, S.O., Jacobs, L.K., Manning, F.C., Tsangaris, T.N., Schwartz, A.M., Kennedy, K.A., and Patierno, S.R. (2000). Overexpression of the glucose-regulated stress gene GRP78 in malignant but not benign human breast lesions. Breast Cancer Res Treat 59, 15-26.
Feun, L., and Savaraj, N. (2006). Pegylated arginine deiminase: a novel anticancer enzyme agent. Expert Opin Investig Drugs 15, 815-822.
Forbes, N.S., Meadows, A.L., Clark, D.S., and Blanch, H.W. (2006). Estradiol stimulates the biosynthetic pathways of breast cancer cells: detection by metabolic flux analysis. Metab Eng 8, 639-652.
Furr, B.J., and Jordan, V.C. (1984). The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 25, 127-205.
Gao, P., Tchernyshyov, I., Chang, T.C., Lee, Y.S., Kita, K., Ochi, T., Zeller, K.I., De Marzo, A.M., Van Eyk, J.E., Mendell, J.T., et al. (2009). c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458, 762-765.
Georgiannos, S.N., Weston, P.M., and Goode, A.W. (1995). Correlation between albuminuria and positively charged amino acids in gastrointestinal cancer. Int Surg 80, 49-52.
Gerner, E.W., and Meyskens, F.L., Jr. (2004). Polyamines and cancer: old molecules, new understanding. Nat Rev Cancer 4, 781-792.
Gillies, R.J., Robey, I., and Gatenby, R.A. (2008). Causes and consequences of increased glucose metabolism of cancers. J Nucl Med 49 Suppl 2, 24S-42S.
Gruber, H.E., Yamaguchi, D., Ingram, J., Leslie, K., Huang, W., Miller, T.A., and Hanley, E.N., Jr. (2002). Expression and localization of estrogen receptor-beta in annulus cells of the human intervertebral disc and the mitogenic effect of 17-beta-estradiol in vitro. BMC Musculoskelet Disord 3, 4.
Harding, H.P., Novoa, I., Zhang, Y., Zeng, H., Wek, R., Schapira, M., and Ron, D. (2000). Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6, 1099-1108.
Harding, H.P., Zhang, Y., and Ron, D. (1999). Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397, 271-274.
Hatzivassiliou, G., Zhao, F., Bauer, D.E., Andreadis, C., Shaw, A.N., Dhanak, D., Hingorani, S.R., Tuveson, D.A., and Thompson, C.B. (2005). ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311-321.
Hitomi, J., Katayama, T., Eguchi, Y., Kudo, T., Taniguchi, M., Koyama, Y., Manabe, T., Yamagishi, S., Bando, Y., Imaizumi, K., et al. (2004). Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. J Cell Biol 165, 347-356.
Howell, A., Robertson, J.F., Quaresma Albano, J., Aschermannova, A., Mauriac, L., Kleeberg, U.R., Vergote, I., Erikstein, B., Webster, A., and Morris, C. (2002). Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 20, 3396-3403.
Hsu, P.P., and Sabatini, D.M. (2008). Cancer cell metabolism: Warburg and beyond. Cell 134, 703-707.
Hulka, B.S., and Stark, A.T. (1995). Breast cancer: cause and prevention. Lancet 346, 883-887.
Ishii, T., Sugita, Y., and Bannai, S. (1987). Regulation of glutathione levels in mouse spleen lymphocytes by transport of cysteine. J Cell Physiol 133, 330-336.
Ishimoto, T., Nagano, O., Yae, T., Tamada, M., Motohara, T., Oshima, H., Oshima, M., Ikeda, T., Asaba, R., Yagi, H., et al. (2011). CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth. Cancer Cell 19, 387-400.
Izzo, F., Marra, P., Beneduce, G., Castello, G., Vallone, P., De Rosa, V., Cremona, F., Ensor, C.M., Holtsberg, F.W., Bomalaski, J.S., et al. (2004). Pegylated arginine deiminase treatment of patients with unresectable hepatocellular carcinoma: results from phase I/II studies. J Clin Oncol 22, 1815-1822.
Jackowski, S. (1994). Coordination of membrane phospholipid synthesis with the cell cycle. J Biol Chem 269, 3858-3867.
Jensen, V., Ladekarl, M., Holm-Nielsen, P., Melsen, F., and Soerensen, F.B. (1995). The prognostic value of oncogenic antigen 519 (OA-519) expression and proliferative activity detected by antibody MIB-1 in node-negative breast cancer. J Pathol 176, 343-352.
Jousse, C., Bruhat, A., Ferrara, M., and Fafournoux, P. (2000). Evidence for multiple signaling pathways in the regulation of gene expression by amino acids in human cell lines. J Nutr 130, 1555-1560.
Kelsey, J.L. (1993). Breast cancer epidemiology: summary and future directions. Epidemiol Rev 15, 256-263.
Kelsey, J.L., and Bernstein, L. (1996). Epidemiology and prevention of breast cancer. Annu Rev Public Health 17, 47-67.
Kim, J.W., Gao, P., Liu, Y.C., Semenza, G.L., and Dang, C.V. (2007). Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol Cell Biol 27, 7381-7393.
Kroemer, G., and Pouyssegur, J. (2008). Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell 13, 472-482.
Kubota, A., Meguid, M.M., and Hitch, D.C. (1992). Amino acid profiles correlate diagnostically with organ site in three kinds of malignant tumors. Cancer 69, 2343-2348.
Kuhajda, F.P. (2006). Fatty acid synthase and cancer: new application of an old pathway. Cancer Res 66, 5977-5980.
Kumar-Sinha, C., Ignatoski, K.W., Lippman, M.E., Ethier, S.P., and Chinnaiyan, A.M. (2003). Transcriptome analysis of HER2 reveals a molecular connection to fatty acid synthesis. Cancer Res 63, 132-139.
Kusakabe, T., Maeda, M., Hoshi, N., Sugino, T., Watanabe, K., Fukuda, T., and Suzuki, T. (2000). Fatty acid synthase is expressed mainly in adult hormone-sensitive cells or cells with high lipid metabolism and in proliferating fetal cells. J Histochem Cytochem 48, 613-622.
Lavanchy, D. (2004). Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat 11, 97-107.
Lee, J.C., Chen, M.J., Chang, C.H., Tiai, Y.F., Lin, P.W., Lai, H.S., and Wang, S.T. (2003). Plasma amino acid levels in patients with colorectal cancers and liver cirrhosis with hepatocellular carcinoma. Hepatogastroenterology 50, 1269-1273.
Lee, Y.R., Park, J., Yu, H.N., Kim, J.S., Youn, H.J., and Jung, S.H. (2005). Up-regulation of PI3K/Akt signaling by 17beta-estradiol through activation of estrogen receptor-alpha, but not estrogen receptor-beta, and stimulates cell growth in breast cancer cells. Biochem Biophys Res Commun 336, 1221-1226.
Lin, C.Y., Vega, V.B., Thomsen, J.S., Zhang, T., Kong, S.L., Xie, M., Chiu, K.P., Lipovich, L., Barnett, D.H., Stossi, F., et al. (2007). Whole-genome cartography of estrogen receptor alpha binding sites. PLoS Genet 3, e87.
Liu, W., Zabirnyk, O., Wang, H., Shiao, Y.H., Nickerson, M.L., Khalil, S., Anderson, L.M., Perantoni, A.O., and Phang, J.M. (2010). miR-23b targets proline oxidase, a novel tumor suppressor protein in renal cancer. Oncogene 29, 4914-4924.
Liu, Y., Borchert, G.L., Donald, S.P., Diwan, B.A., Anver, M., and Phang, J.M. (2009). Proline oxidase functions as a mitochondrial tumor suppressor in human cancers. Cancer Res 69, 6414-6422.
Liu, Y., Borchert, G.L., Surazynski, A., and Phang, J.M. (2008). Proline oxidase, a p53-induced gene, targets COX-2/PGE2 signaling to induce apoptosis and inhibit tumor growth in colorectal cancers. Oncogene 27, 6729-6737.
Lobo, C., Ruiz-Bellido, M.A., Aledo, J.C., Marquez, J., Nunez De Castro, I., and Alonso, F.J. (2000). Inhibition of glutaminase expression by antisense mRNA decreases growth and tumourigenicity of tumour cells. Biochem J 348 Pt 2, 257-261.
Ma, W.W., Jacene, H., Song, D., Vilardell, F., Messersmith, W.A., Laheru, D., Wahl, R., Endres, C., Jimeno, A., Pomper, M.G., et al. (2009). [18F]fluorodeoxyglucose positron emission tomography correlates with Akt pathway activity but is not predictive of clinical outcome during mTOR inhibitor therapy. J Clin Oncol 27, 2697-2704.
Ma, Y., Brewer, J.W., Diehl, J.A., and Hendershot, L.M. (2002). Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J Mol Biol 318, 1351-1365.
Ma, Y., and Hendershot, L.M. (2004). The role of the unfolded protein response in tumour development: friend or foe? Nat Rev Cancer 4, 966-977.
Masetti, R., and Pession, A. (2009). First-line treatment of acute lymphoblastic leukemia with pegasparaginase. Biologics 3, 359-368.
Matoba, S., Kang, J.G., Patino, W.D., Wragg, A., Boehm, M., Gavrilova, O., Hurley, P.J., Bunz, F., and Hwang, P.M. (2006). p53 regulates mitochondrial respiration. Science 312, 1650-1653.
Matsumoto, K., Obara, N., Ema, M., Horie, M., Naka, A., Takahashi, S., and Imagawa, S. (2009). Antitumor effects of 2-oxoglutarate through inhibition of angiogenesis in a murine tumor model. Cancer Sci 100, 1639-1647.
Maxwell, S.A., and Davis, G.E. (2000). Differential gene expression in p53-mediated apoptosis-resistant vs. apoptosis-sensitive tumor cell lines. Proc Natl Acad Sci U S A 97, 13009-13014.
McCullough, K.D., Martindale, J.L., Klotz, L.O., Aw, T.Y., and Holbrook, N.J. (2001). Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol 21, 1249-1259.
McLeod, S.D., Ranson, M., and Mason, R.S. (1994). Effects of estrogens on human melanocytes in vitro. J Steroid Biochem Mol Biol 49, 9-14.
Medes, G., Thomas, A., and Weinhouse, S. (1953). Metabolism of neoplastic tissue. IV. A study of lipid synthesis in neoplastic tissue slices in vitro. Cancer Res 13, 27-29.
Menendez, J.A., and Lupu, R. (2004). Fatty acid synthase-catalyzed de novo fatty acid biosynthesis: from anabolic-energy-storage pathway in normal tissues to jack-of-all-trades in cancer cells. Arch Immunol Ther Exp (Warsz) 52, 414-426.
Menendez, J.A., and Lupu, R. (2007). Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7, 763-777.
Menendez, J.A., Oza, B.P., Colomer, R., and Lupu, R. (2005). The estrogenic activity of synthetic progestins used in oral contraceptives enhances fatty acid synthase-dependent breast cancer cell proliferation and survival. Int J Oncol 26, 1507-1515.
Moreno-Sanchez, R., Rodriguez-Enriquez, S., Marin-Hernandez, A., and Saavedra, E. (2007). Energy metabolism in tumor cells. Febs J 274, 1393-1418.
Naini, A.B., Dickerson, J.W., and Brown, M.M. (1988). Preoperative and postoperative levels of plasma protein and amino acid in esophageal and lung cancer patients. Cancer 62, 355-360.
Ni, Y., Schwaneberg, U., and Sun, Z.H. (2008). Arginine deiminase, a potential anti-tumor drug. Cancer Lett 261, 1-11.
Norton, J.A., Gorschboth, C.M., Wesley, R.A., Burt, M.E., and Brennan, M.F. (1985). Fasting plasma amino acid levels in cancer patients. Cancer 56, 1181-1186.
Nowak, M.A., Bonhoeffer, S., Hill, A.M., Boehme, R., Thomas, H.C., and McDade, H. (1996). Viral dynamics in hepatitis B virus infection. Proc Natl Acad Sci U S A 93, 4398-4402.
Onuma, T., Waligunda, J., and Holland, J.F. (1971). Amino acid requirements in vitro of human leukemic cells. Cancer Res 31, 1640-1644.
Osborne, C.K., Schiff, R., Fuqua, S.A., and Shou, J. (2001). Estrogen receptor: current understanding of its activation and modulation. Clin Cancer Res 7, 4338s-4342s; discussion 4411s-4412s.
Osthus, R.C., Shim, H., Kim, S., Li, Q., Reddy, R., Mukherjee, M., Xu, Y., Wonsey, D., Lee, L.A., and Dang, C.V. (2000). Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem 275, 21797-21800.
Pearlstone, D.B., Lee, J.I., Alexander, R.H., Chang, T.H., Brennan, M.F., and Burt, M. (1995). Effect of enteral and parenteral nutrition on amino acid levels in cancer patients. JPEN J Parenter Enteral Nutr 19, 204-208.
Perlmutter, D.H. (1999). Misfolded proteins in the endoplasmic reticulum. Lab Invest 79, 623-638.
Phang, J.M., Liu, W., and Zabirnyk, O. (2010). Proline metabolism and microenvironmental stress. Annu Rev Nutr 30, 441-463.
Phillips, T.M., McBride, W.H., and Pajonk, F. (2006). The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst 98, 1777-1785.
Pollari, S., Kakonen, S.M., Edgren, H., Wolf, M., Kohonen, P., Sara, H., Guise, T., Nees, M., and Kallioniemi, O. (2011). Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis. Breast Cancer Res Treat 125, 421-430.
Polyak, K., Xia, Y., Zweier, J.L., Kinzler, K.W., and Vogelstein, B. (1997). A model for p53-induced apoptosis. Nature 389, 300-305.
Proenza, A.M., Oliver, J., Palou, A., and Roca, P. (2003). Breast and lung cancer are associated with a decrease in blood cell amino acid content. J Nutr Biochem 14, 133-138.
Saito, S., Furuno, A., Sakurai, J., Sakamoto, A., Park, H.R., Shin-Ya, K., Tsuruo, T., and Tomida, A. (2009). Chemical genomics identifies the unfolded protein response as a target for selective cancer cell killing during glucose deprivation. Cancer Res 69, 4225-4234.
Semenza, G.L. (2009). Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin Cancer Biol 19, 12-16.
Shen, J., Chen, X., Hendershot, L., and Prywes, R. (2002). ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell 3, 99-111.
Shi, Y., Vattem, K.M., Sood, R., An, J., Liang, J., Stramm, L., and Wek, R.C. (1998). Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol 18, 7499-7509.
Shimoda, R., Nagashima, M., Sakamoto, M., Yamaguchi, N., Hirohashi, S., Yokota, J., and Kasai, H. (1994). Increased formation of oxidative DNA damage, 8-hydroxydeoxyguanosine, in human livers with chronic hepatitis. Cancer Res 54, 3171-3172.
Shuda, M., Kondoh, N., Imazeki, N., Tanaka, K., Okada, T., Mori, K., Hada, A., Arai, M., Wakatsuki, T., Matsubara, O., et al. (2003). Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis. J Hepatol 38, 605-614.
Sidrauski, C., and Walter, P. (1997). The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response. Cell 90, 1031-1039.
Smith, I.E., and Dowsett, M. (2003). Aromatase inhibitors in breast cancer. N Engl J Med 348, 2431-2442.
Snell, K. (1985). Enzymes of serine metabolism in normal and neoplastic rat tissues. Biochim Biophys Acta 843, 276-281.
Snell, K., Natsumeda, Y., Eble, J.N., Glover, J.L., and Weber, G. (1988). Enzymic imbalance in serine metabolism in human colon carcinoma and rat sarcoma. Br J Cancer 57, 87-90.
Song, M.S., Park, Y.K., Lee, J.H., and Park, K. (2001). Induction of glucose-regulated protein 78 by chronic hypoxia in human gastric tumor cells through a protein kinase C-epsilon/ERK/AP-1 signaling cascade. Cancer Res 61, 8322-8330.
Sreekumar, A., Poisson, L.M., Rajendiran, T.M., Khan, A.P., Cao, Q., Yu, J., Laxman, B., Mehra, R., Lonigro, R.J., Li, Y., et al. (2009). Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 457, 910-914.
Suzuki, S., Tanaka, T., Poyurovsky, M.V., Nagano, H., Mayama, T., Ohkubo, S., Lokshin, M., Hosokawa, H., Nakayama, T., Suzuki, Y., et al. (2010). Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci U S A 107, 7461-7466.
Swinnen, J.V., Brusselmans, K., and Verhoeven, G. (2006). Increased lipogenesis in cancer cells: new players, novel targets. Curr Opin Clin Nutr Metab Care 9, 358-365.
Swinnen, J.V., Esquenet, M., Goossens, K., Heyns, W., and Verhoeven, G. (1997). Androgens stimulate fatty acid synthase in the human prostate cancer cell line LNCaP. Cancer Res 57, 1086-1090.
Swinnen, J.V., Heemers, H., Deboel, L., Foufelle, F., Heyns, W., and Verhoeven, G. (2000). Stimulation of tumor-associated fatty acid synthase expression by growth factor activation of the sterol regulatory element-binding protein pathway. Oncogene 19, 5173-5181.
Tan, M.C., Linehan, D.C., Hawkins, W.G., Siegel, B.A., and Strasberg, S.M. (2007). Chemotherapy-induced normalization of FDG uptake by colorectal liver metastases does not usually indicate complete pathologic response. J Gastrointest Surg 11, 1112-1119.
Tong, L. (2005). Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery. Cell Mol Life Sci 62, 1784-1803.
Van de Sande, T., De Schrijver, E., Heyns, W., Verhoeven, G., and Swinnen, J.V. (2002). Role of the phosphatidylinositol 3'-kinase/PTEN/Akt kinase pathway in the overexpression of fatty acid synthase in LNCaP prostate cancer cells. Cancer Res 62, 642-646.
Vander Heiden, M.G., Cantley, L.C., and Thompson, C.B. (2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029-1033.
Vie, N., Copois, V., Bascoul-Mollevi, C., Denis, V., Bec, N., Robert, B., Fraslon, C., Conseiller, E., Molina, F., Larroque, C., et al. (2008). Overexpression of phosphoserine aminotransferase PSAT1 stimulates cell growth and increases chemoresistance of colon cancer cells. Mol Cancer 7, 14.
Visca, P., Sebastiani, V., Botti, C., Diodoro, M.G., Lasagni, R.P., Romagnoli, F., Brenna, A., De Joannon, B.C., Donnorso, R.P., Lombardi, G., et al. (2004). Fatty acid synthase (FAS) is a marker of increased risk of recurrence in lung carcinoma. Anticancer Res 24, 4169-4173.
Vousden, K.H., and Ryan, K.M. (2009). p53 and metabolism. Nat Rev Cancer 9, 691-700.
Wang, H.G., Pathan, N., Ethell, I.M., Krajewski, S., Yamaguchi, Y., Shibasaki, F., McKeon, F., Bobo, T., Franke, T.F., and Reed, J.C. (1999). Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 284, 339-343.
Wang, J.B., Erickson, J.W., Fuji, R., Ramachandran, S., Gao, P., Dinavahi, R., Wilson, K.F., Ambrosio, A.L., Dias, S.M., Dang, C.V., et al. (2010). Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 18, 207-219.
Wang, T.T., and Phang, J.M. (1995). Effects of estrogen on apoptotic pathways in human breast cancer cell line MCF-7. Cancer Res 55, 2487-2489.
Warburg, O. (1956). On the origin of cancer cells. Science 123, 309-314.
Waris, G., Tardif, K.D., and Siddiqui, A. (2002). Endoplasmic reticulum (ER) stress: hepatitis C virus induces an ER-nucleus signal transduction pathway and activates NF-kappaB and STAT-3. Biochem Pharmacol 64, 1425-1430.
Watanabe, A., Higashi, T., Sakata, T., and Nagashima, H. (1984). Serum amino acid levels in patients with hepatocellular carcinoma. Cancer 54, 1875-1882.
Xu, Z., Jensen, G., and Yen, T.S. (1997). Activation of hepatitis B virus S promoter by the viral large surface protein via induction of stress in the endoplasmic reticulum. J Virol 71, 7387-7392.
Yamanaka, H., Kanemaki, T., Tsuji, M., Kise, Y., Hatano, T., Hioki, K., and Yamamoto, M. (1990). Branched-chain amino acid-supplemented nutritional support after gastrectomy for gastric cancer with special reference to plasma amino acid profiles. Nutrition 6, 241-245.
Yang, C., Sudderth, J., Dang, T., Bachoo, R.M., McDonald, J.G., and DeBerardinis, R.J. (2009). Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling. Cancer Res 69, 7986-7993.
Yoshida, H., Matsui, T., Yamamoto, A., Okada, T., and Mori, K. (2001). XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107, 881-891.
Zhong, H., Chiles, K., Feldser, D., Laughner, E., Hanrahan, C., Georgescu, M.M., Simons, J.W., and Semenza, G.L. (2000). Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 60, 1541-1545.
Zong, W.X., Li, C., Hatzivassiliou, G., Lindsten, T., Yu, Q.C., Yuan, J., and Thompson, C.B. (2003). Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. J Cell Biol 162, 59-69.