62
Acknowledgements
I am deeply grateful to Associate Professor Kazuichi Sakamoto, University of Tsukuba for his
continuous guidance and valuable discussion throughout my doctoral program.,
I am grateful to Associate Professors Hidekazu Kuwayama and Kyouichi Sawamura and
Professor Kenji Miura, University of Tsukuba for their guidance and valuable discussion.
I also thank Drs. Hideo Araki, Yoshinori Ishikawa, Satoshi Kitazawa, Akito Hata, Yoshihiko
Satoh, Yukiko Yamamoto, Kohei Honda, Kazuyo Kakoi, Keisuke Imamura, Masako Sasaki, Ikuo
Miyahisa, Yoshinori Satomi, Ryuuichi Nishigaki, Megumi Hirayama, Kazunobu Aoyama, Hironobu
Maezaki, and my colleagues in Takeda Pharmaceutical Company Limited for valuable suggestions,
contributions and helpful supports.
I am thankful to Drs. Shunsuke Ebara, Yoji Sagiya, Kousei Toyoshima, Koji Yamamoto, Shinichi
Matsumoto, Naomi Kamiguchi, and Akito Kadotani for the excellent technical support.
I appreciate Professor Tomoyoshi Soga, Keio University for conducting metabolomic analysis.
I especially thank Drs. Takahito Hara and Hiroyuki Sumi for the discussions, suggestions, and
helpful supports.
64 References
Aldana B.I.,2019. Microglia-Specific Metabolic Changes in Neurodegeneration. J Mol Biol. 431,
1830-1842.
Angelucci C., D'Alessio A. Iacopino F. Proietti G. Di Leone A. Masetti R. Sica G.,2018. Pivotal role
of human stearoyl-CoA desaturases (SCD1 and 5) in breast cancer progression: oleic acid-based
effect of SCD1 on cell migration and a novel pro-cell survival role for SCD5. Oncotarget. 9,
24364-24380.
Anderson M.E., Meister A.,1989. Glutathione monoesters. Anal Biochem. 183, 16-20.
Astarita G., Jung K.M., Vasilevko V., Dipatrizio N.V., Martin S.K., Cribbs D.H., Head E., Cotman
C.W., Piomelli D.,2011. Elevated stearoyl-CoA desaturase in brains of patients with
Alzheimer's disease. PLoS One. 6, e24777.
Bailey H.H., Mulcahy R.T., Tutsch K.D., Arzoomanian R.Z., Alberti D., Tombes M.B., Wilding G.,
Pomplun M., Spriggs D.R.,1994. Phase I clinical trial of intravenous L-buthionine sulfoximine
and melphalan: an attempt at modulation of glutathione. J. Clin. Oncol. 12, 194–205.
Bailey H.H., Ripple G., Tutsch K.D., Arzoomanian R.Z., Alberti D., Feierabend C., Mahvi D., Schink
J., Pomplun M., Mulcahy R.T., et al..1997. Phase I study of continuous-infusion
L-S,R-buthionine sulfoximine with intravenous melphalan. J. Natl. Cancer Inst. 89, 1789–1796.
Bligh, E.G., Dyer, W.J.,1959. A rapid method of total lipid extraction and purification. Can. J. Biochem.
Physiol. 37, 911–917.
Boroughs L.K., DeBerardinis R.J.,2015. Metabolic pathways promoting cancer cell survival and
growth. Nat Cell Biol. 17, 351-359.
Cairns R.A., Harris I.S., Mak T.W.,2011. Regulation of cancer cell metabolism. Nat. Rev. Cancer. 11,
85–95.
Chen L., Ren J., Yang L., Li Y., Fu J., Li Y., Tian Y., Qiu F., Liu Z., Qiu Y.,2016. Stearoyl-CoA
desaturase-1 mediated cell apoptosis in colorectal cancer by promoting ceramide synthesis. Sci
Rep. 6, 19665.
Choi, J.M., Kim, T.E., Cho, J.Y., Lee, H.J., Jung, B.H.,2014. Development of lipidomic platform and
phosphatidylcholine retention time index for lipid profiling of rosuvastatin treated human
plasma. J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci. 944, 157–165.
Courtnay R., Ngo D.C., Malik N., Ververis K., Tortorella S.M., Karagiannis T.C.,2015. Cancer
metabolism and the Warburg effect: the role of HIF-1 and PI3K. Mol. Biol. Rep. 42, 841-851.
Currie, E., Schulze, A., Zechner, R., Walther, T.C., Farese, R.V. Jr.,2013. Cellular fatty acid
metabolism and cancer. Cell. Metab. 18, 153–161.
Dalton T.P., Dieter M.Z., Yang Y., Shertzer H.G., Nebert D.W.,2000. Knockout of the mouse
glutamate cysteine ligase catalytic subunit (Gclc) gene: embryonic lethal when homozygous,
and proposed model for moderate glutathione deficiency when heterozygous. Biochem Biophys
66 Res Commun. 279, 324-329.
de Brachène A.C., Dif N., de Rocca Serra A., Bonnineau C., Velghe A.I., Larondelle Y., Tyteca D.,
Demoulin J.B.,2017. PDGF-induced fibroblast growth requires monounsaturated fatty acid
production by stearoyl-CoA desaturase. FEBS Open Bio. 7, 414-423.
Denkert C., Budczies J., Weichert W., Wohlgemuth G., Scholz M., Kind T., Niesporek S., Noske A.,
Buckendahl A., Dietel M., et al.,2008. Metabolite profiling of human colon carcinoma –
deregulation of TCA cycle and amino acid turnover. Mol. Cancer. 7, 72.
Díaz D., Krejsa C.M., Kavanagh T.J.,2002. Expression of glutamate-cysteine ligase during mouse
development. Mol Reprod Dev. 62, 83-91.
Dienstmann, R., Rodon, J., Tabernero, J.,2013. Biomarker-driven patient selection for early clinical
trials. Curr. Opin. Oncol. 25, 305–312.
Dixon S.J., Lemberg K.M., Lamprecht M.R., Skouta R., Zaitsev E.M., Gleason C.E., Patel D.N., Bauer
A.J., Cantley A.M., Yang W.S., et al.,2012. Ferroptosis: An iron-dependent form of nonapoptotic
cell death. Cell. 149, 1060–1072.
Du X., Wang Q.R., Chan E., Merchant M., Liu J., French D., Ashkenazi A., Qing J.,2012. FGFR3
stimulates stearoyl CoA desaturase 1 activity to promote bladder tumor growth. Cancer Res. 72,
5843-5855.
Ducheix S., Peres C., Härdfeldt J., Frau C., Mocciaro G., Piccinin E., Lobaccaro J.M., De Santis S.,
Chieppa M., Bertrand-Michel J., et al.,2018. Deletion of Stearoyl-CoA Desaturase-1 From the
Intestinal Epithelium Promotes Inflammation and Tumorigenesis, Reversed by Dietary Oleate.
Gastroenterology. 155, 1524-1538.
Ettcheto M., Cano A., Busquets O., Manzine P.R., Sánchez-López E., Castro-Torres R.D., Beas-Zarate
C., Verdaguer E., García M.L., Olloquequi J., et al.,2019. A metabolic perspective of late onset
Alzheimer's disease. Pharmacol Res.145, 104255.
Evans M., Brown J., McIntosh M.,2002. Isomer-specific effects of conjugated linoleic acid (CLA) on
adiposity and lipid metabolism. J Nutr Biochem. 13, 508.
Ferreri C., Masi A., Sansone A., Giacometti G., Larocca A.V., Menounou G., Scanferlato R.,
Tortorella S., Rota D., Conti M., et al.,2017. Fatty Acids in Membranes as Homeostatic,
Metabolic and Nutritional Biomarkers: Recent Advancements in Analytics and Diagnostics.
Diagnostics (Basel). 7, 1.
Franklin C.C., Backos D.S., Mohar I., White C.C., Forman H.J., Kavanagh T.J.,2009. Structure,
function, and post-translational regulation of the catalytic and modifier subunits of glutamate
cysteine ligase. Mol Aspects Med. 30, 86-98.
Fritz, V., Benfodda, Z., Rodier, G., Henriquet, C., Iborra, F., Avancès, C., Allory, Y, de la Taille, A.,
Culine, S., Blancou, H., et al., 2010. Abrogation of de novo lipogenesis by stearoyl-CoA
desaturase 1 inhibition interferes with oncogenic signaling and blocks prostate cancer
68 progression in mice. Mol. Cancer Ther. 9, 1740–1754.
Gainor, J.F., Longo, D.L., Chabner, B.A.,2014. Pharmacodynamic biomarkers: falling short of the
mark? Clin. Cancer. Res. 20, 2587–2594.
Griffiths, B., Lewis, C.A., Bensaad, K., Ros, S., Zhang, Q., Ferber, E.C., Konisti, S., Peck, B.,
Miess, H., East, P., et al.,2013. Sterol regulatory element binding protein-dependent regulation
of lipid synthesis supports cell survival and tumor growth. Cancer Metab. 1, 3.
Gu Z., Suburu J., Chen H., Chen Y.Q.,2013. Mechanisms of omega-3 polyunsaturated fatty acids in
prostate cancer prevention. Biomed Res Int. 824563.
Haase V.H.,2009. The VHL Tumor Suppressor: Master Regulator of HIF. Curr. Pharm. Des. 15, 3895–
3903.
Hakimi A.A., Reznik E., Lee C.H., Creighton C.J., Brannon A.R., Luna A., Aksoy B.A., Liu E.M.,
Shen R., Lee W., et al.,2016. An integrated metabolic atlas of clear cell renal cell carcinoma.
Cancer Cell. 29, 104–116.
Han J., Kaufman R.J.,2016. The role of ER stress in lipid metabolism and lipotoxicity. J Lipid Res. 57,
1329-1338.
Hess D., Chisholm J.W., Igal R.A., 2010. Inhibition of stearoylCoA desaturase activity blocks cell
cycle progression and induces programmed cell death in lung cancer cells. PLoS One. 5, e11394.
Howie D., Ten Bokum A., Necula A.S., Cobbold P., Waldmann H.,2018. The Role of Lipid
Metabolism in T Lymphocyte Differentiation and Survival. Front Immunol. 8, 1949.
Huang, G.M., Jiang, Q.H., Cai, C., Qu, M., Shen, W.,2015. SCD1 negatively regulates
autophagy-induced cell death in human hepatocellular carcinoma through inactivation of the AMPK
signaling pathway. Cancer Lett. 358, 180–190.
Huang, J., Fan, X.X., He, J., Pan, H., Li, R.Z., Huang, L., Jiang, Z., Yao, X.J., Liu, L., Leung, E.L.,
He, J.X.,2016. SCD1 is associated with tumor promotion, late stage and poor survival in lung
adenocarcinoma. Oncotarget. 7, 39970–39979.
Hummel, J., Segu, S., Li, Y., Irgang, S., Jueppner, J., Giavalisco, P.,2011. Ultra performance liquid
chromatography and high resolution mass spectrometry for the analysis of plant lipids. Front.
Plant Sci. 2, 54.
Ide, Y., Waki, M., Hayasaka, T., Nishio, T., Morita, Y., Tanaka, H., Sasaki, T., Koizumi, K.,
Matsunuma, R., Hosokawa, Y., et al.,2013. Human breast cancer tissues contain abundant
phosphatidylcholine(36:1) with high stearoyl-CoA desaturase-1 expression. PLoS One. 8,
e61204.
Igal, R.A.,2016. Stearoyl CoA desaturase-1: New insights into a central regulator of cancer
metabolism. Biochim. Biophys. Acta. 1861, 1865–1880.
Imamura, K., Tomita, N., Ito, Y., Ono, K., Maezaki, H., Nii, N.,2015. Pyridazine compound. World
patent WO2015137385 A1.
70
Imamura K., Tomita N., Kawakita Y., Ito Y., Ono K., Nii N., Miyazaki T., Yonemori K., Tawada M.,
Sumi H., et al.,2017. Discovery of Novel and Potent Stearoyl Coenzyme A Desaturase 1
(SCD1) Inhibitors as Anticancer Agents. Bioorg Med Chem. 25, 3768-3779.
Karlenius TC, Tonissen KF.,2010. Thioredoxin and Cancer: A Role for Thioredoxin in all States of
Tumor Oxygenation. Cancers (Basel). 2, 209-232.
Kim S.J., Choi H., Park S.S., Chang C., Kim E.,2011. Stearoyl CoA desaturase (SCD) facilitates
proliferation of prostate cancer cells through enhancement of androgen receptor transactivation.
Mol Cells. 31, 371-377.
Kong H., Chandel N.S.,2018. Regulation of redox balance in cancer and T cells. J Biol Chem. 293,
7499-7507.
Kurikawa N., Takagi T., Wakimoto S., Uto Y., Terashima H., Kono K., Ogata T., Ohsumi J.,2013. A
novel inhibitor of stearoyl-CoA desaturase-1 attenuates hepatic lipid accumulation, liver injury
and inflammation in model of nonalcoholic steatohepatitis. Biol Pharm Bull. 36, 259-267.
Lai K.K.Y., Kweon S.M., Chi F., Hwang E., Kabe Y., Higashiyama R., Qin L., Yan R., Wu R.P., Lai
K., Fujii N., et al.,2017. Stearoyl-CoA Desaturase Promotes Liver Fibrosis and Tumor
Development in Mice via a Wnt Positive-Signaling Loop by Stabilization of Low-Density
Lipoprotein-Receptor-Related Proteins 5 and 6. Gastroenterology. 152, 1477-1491.
Lau A., Villeneuve N.F., Sun Z., Wong P.K., Zhang D.D.,2008. Dual roles of Nrf2 in cancer. Pharmacol
Res. 58, 262-270.
Lagace T.A., Ridgway N.D. 2013. The Role of Phospholipids in the Biological Activity and Structure
of the Endoplasmic Reticulum. Biochim. Biophys. Acta., 1833, 2499-2510
Lengi A.J., Corl B.A.,2007. Identification and characterization of a novel bovine stearoyl-CoA
desaturase isoform with homology to human SCD5. Lipids. 42, 499-508.
Liang G.Y., Lu S.X., Xu G., Liu X.D., Li J,. Zhang D.S.,2013. Expression of metallothionein and Nrf2
pathway genes in lung cancer and cancer-surrounding tissues. World J Surg Oncol. 11, 199.
Liou G.Y., Storz P.,2010. Reactive oxygen species in cancer. Free Radic Res. 44, 479-496.
Liu, G., Lynch, J.K., Freeman, J., Liu, B., Xin, Z., Zhao, H., Serby, M.D., Kym, P.R., Suhar, T.S.,
Smith, H.T., et al.,2007. Discovery of potent, selective, orally bioavailable stearoyl-CoA
desaturase 1 inhibitors. J. Med. Chem. 50, 3086–3100.
Liu J.J., Green P., John Mann J., Rapoport S.I. Sublette M.E.,2015. Pathways of polyunsaturated
fatty acid utilization: implications for brain function in neuropsychiatric health and disease.
Brain Res. 1597, 220-246.
Lounis M.A., Escoula Q., Veillette C., Bergeron K.F., Ntambi J.M., Mounier C.,2016. SCD1
deficiency protects mice against ethanol-induced liver injury. Biochim Biophys Acta. 1861,
1662-1670.
Lu S.C.,2013. Glutathione synthesis. Biochim. Biophys. Acta. 1830, 3143–3153.
72
Mashima, T., Seimiya, H., Tsuruo, T.,2009. De novo fatty-acid synthesis and related pathways as
molecular targets for cancer therapy. Br. J. Cancer. 100, 1369–1372.
Mason, P., Liang, B., Li, L., Fremgen, T., Murphy, E., Quinn, A., Madden, S.L., Biemann, H.P.,
Wang, B., Cohen, A., et al., Booker, M., Lillie, J., Carter, K.,2012. SCD1 inhibition causes
cancer cell death by depleting mono-unsaturated fatty acids. PLoS One. 7, e33823.
Maulucci, G., Cohen, O., Daniel, B., Sansone, A., Petropoulou, P.I., Filou, S., Spyridonidis, A., Pani,
G., De Spirito, M., Chatgilialoglu, C., et al.,2016. Fatty acid-related modulations of membranes
fluidity in cells: detection and implications. Free Radic. Res. 50, S40–S50.
Mehta, S., Shelling, A., Muthukaruppan, A., Lasham, A., Blenkiron, C., Laking, G., Print, C.,2012.
Predictive and prognostic molecular markers for cancer medicine. Ther. Adv. Med. Oncol. 2,
125–148.
Minville-Walz, M., Pierre, A.S., Pichon, L., Bellenger, S., Fèvre, C., Bellenger, J., Tessier, C., Narce,
M., Rialland, M.,2010. Inhibition of stearoyl-CoA desaturase 1 expression induces
CHOP-dependent cell death in human cancer cells. PLoS One. 5, e14363.
Miyahisa, I. Suzuki, H., Mizukami, A., Tanaka, Y., Ono, M., Hixon, M.S., Matsui, J., 2016.
T-3364366 targets the desaturase domain of delta-5 desaturase with nanomolar potency and a
multihour residence time. ACS Med. Chem. Lett. 7, 868–872.
Mohammadzadeh, F., Mosayebi, G., Montazeri, V., Darabi, M., Fayezi, S., Shaaker, M., Rahmati,
M., Baradaran, B., Mehdizadeh, A., Darabi, M.,2014. Fatty acid composition of tissue cultured
breast carcinoma and the effect of stearoyl-CoA desaturase 1 inhibition. J. Breast Cancer. 17,
136–142.
Moore S., Knudsen B., True L.D., Hawley S., Etzioni R., Wade C., Gifford D., Coleman I., Nelson
P.S.,2005. Loss of stearoyl-CoA desaturase expression is a frequent event in prostate carcinoma.
Int J Cancer. 114, 563-571.
Mougiakakos D., Okita R., Ando T., Dürr C., Gadiot J., Ichikawa J., Zeiser R., Blank C., Johansson
C.C., Kiessling R.,2012. High expression of GCLC is associated with malignant melanoma of
low oxidative phenotype and predicts a better prognosis. J Mol Med (Berl). 90, 935-944.
Mounier, C., Bouraoui, L., Rassart, E.,2014. Lipogenesis in cancer progression (review). Int. J.
Oncol. 45, 485–492.
Mouritsen, O.G.,2005. Life – As a matter of fat. Springer-Verlag, Berlin/Heidelberg.
Muñoz-Pinedo C., El Mjiyad N., Ricci J.E.,2012. Cancer metabolism: current perspectives and future
directions. Cell. Death. Dis. 3, e248.
Nagao K., Murakami A., Umeda M.,2019. Structure and Function of Δ9-Fatty Acid Desaturase.
Chem Pharm Bull (Tokyo). 2019;67, 327-332.
Nicolussi A., D'Inzeo S., Capalbo C., Giannini G., Coppa A.,2017. The role of peroxiredoxins in
74 cancer. Mol Clin Oncol. 6, 139-153.
Ntambi J.M., Miyazaki M., Dobrzyn A.,2004. Regulation of stearoyl-CoA desaturase expression.
Lipids. 39, 1061-1065.
Oballa R.M., Belair L., Black W.C., Bleasby K., Chan C.C., Desroches C., Du X., Gordon R., Guay
J., Guiral S., et al.,2011. Development of a liver-targeted stearoyl-CoA desaturase (SCD)
inhibitor (MK-8245) to establish a therapeutic window for the treatment of diabetes and
dyslipidemia. J Med Chem. 54, 5082-5096.
Ogiwara H, Takahashi K, Sasaki M, Kuroda T, Yoshida H, Watanabe R, Maruyama A, Makinoshima
H, Chiwaki F, Sasaki H, et al.,2019. Targeting the Vulnerability of Glutathione Metabolism in
ARID1A-Deficient Cancers. Cancer Cell. 35, 177-190.e8.
Ono A., Sano O., Kazetani K.I., Muraki T., Imamura K., Sumi H., Matsui J., Iwata H.,2017.
Feedback activation of AMPK-mediated autophagy acceleration is a key resistance mechanism
against SCD1 inhibitor-induced cell growth inhibition. PLoS One. 12, e0181243.
Oshino N., Imai Y., Sato R.,1971. A Function of Cytochrome b5 in Fatty Acid Desaturation by Rat
Liver Microsomes. J Biochem. 69, 155-167.
Pampalakis, G., Politi, A.L., Papanastasiou, A., Sotiropoulou, G.,2015. Distinct cholesterogenic and
lipidogenic gene expression patterns in ovarian cancer - a new pool of biomarkers. Genes
Cancer. 6, 472–479.
Paton C.M., Ntambi J.M., 2009. Biochemical and physiological function of stearoyl-CoA desaturase.
Am. J. Physiol. Endocrinol. Metab. 297, E28–E37.
Patra K.C., Hay N.,2014. The pentose phosphate pathway and cancer. Trends. Biochem. Sci. 39,
347-354.
Peck, B., Schug, Z.T., Zhang, Q., Dankworth, B., Jones, D.T., Smethurst, E., Patel, R., Mason, S.,
Jiang, M., Saunders, R., et al.,2016. Inhibition of fatty acid desaturation is detrimental to cancer
cell survival in metabolically compromised environments. Cancer Metab. 4, 6.
Piao C., Cui X., Zhan B., Li J., Li Z., Li Z., Liu X., Bi J., Zhang Z., Kong C. 2019. Inhibition of
Stearoyl CoA desaturase-1 Activity Suppresses Tumour Progression and Improves Prognosis in
Human Bladder Cancer. J Cell Mol. Med., 23, 2064-2076.
Pisanu M.E., Maugeri-Saccà M., Fattore L., Bruschini S., De Vitis C., Tabbì E., Bellei B., Migliano
E., Kovacs D., Camera E., et al.,2018. Inhibition of Stearoyl-CoA desaturase 1 reverts BRAF and
MEK inhibition-induced selection of cancer stem cells in BRAF-mutated melanoma. J Exp Clin
Cancer Res. 37, 318.
Rios-Esteves J, Resh MD.,2013. Stearoyl CoA desaturase is required to produce active,
lipid-modified Wnt proteins. Cell Rep. 4, 1072-1081.
Rogowski, M.P., Flowers, M.T., Stamatikos, A.D., Ntambi, J.M., Paton, C.M.,2013. SCD1 activity in
muscle increases triglyceride PUFA content, exercise capacity, and PPARδ expression in mice. J.
76 Lipid. Res. 54, 2636–2646.
Rojas, C., Pan-Castillo, B., Valls, C., Pujadas, G., Garcia-Vallve, S., Arola, L., Mulero, M.,2014.
Resveratrol enhances palmitate-induced ER stress and apoptosis in cancer cells. PLoS One. 9,
e113929.
Roongta, U.V., Pabalan, J.G., Wang, X., Ryseck, R.P., Fargnoli, J., Henley, B.J., Yang, W.P., Zhu, J.,
Madireddi, M.T., Lawrence, R.M., Wong, T.W., Rupnow, B.A.,2011. Cancer cell dependence on
unsaturated fatty acids implicates stearoyl-CoA desaturase as a target for cancer therapy. Mol.
Cancer Res. 9, 1551–1561.
Rui L.,2014. Energy metabolism in the liver. Compr Physiol. 4, 177-197.
Ruiz-Negrón N., Wander C., McAdam-Marx C., Pesa J., Bailey R.A., Bellows B.K.,2019. Factors
Associated with Diabetes-Related Clinical Inertia in a Managed Care Population and Its Effect
on Hemoglobin A1c Goal Attainment: A Claims-Based Analysis. J Manag Care Spec Pharm.
25, 304-313.
Russo P., Del Bufalo A., Fini M.,2015. Deep sea as a source of novel-anticancer drugs: update on
discovery and preclinical/clinical evaluation in a systems medicine perspective. EXCLI J. 14,
228-236.
Sampath H., Ntambi J.,2008. Role of stearoyl-CoA desaturase in human metabolic disease. Future
Lipidology. 3, 163-173
Satoh K., Yachida S., Sugimoto M., Oshima M., Nakagawa T., Akamoto S., Tabata S., Saitoh K., Kato
K., Sato S., et al.,2017. Global metabolic reprogramming of colorectal cancer occurs at adenoma
stage and is induced by MYC. Proc. Natl. Acad. Sci. U S A. 114, E7697-7706.
Scaglia N., Igal R.A.,2008. Inhibition of Stearoyl-CoA Desaturase 1 expression in human lung
adenocarcinoma cells impairs tumorigenesis. Int J Oncol. 33, 839-850.
Schmidt, K.T., Chau, C.H., Price, D.K., Figg, W.D.,2016. Precision oncology medicine: the clinical
relevance of patient-specific biomarkers used to optimize cancer treatment. J. Clin. Pharmacol.
56, 1484–1499.
Shin C.S., Mishra P., Watrous J.D., Carelli V., D'Aurelio M., Jain M., Chan D.C.,2017. The
glutamate/cystine xCT antiporter antagonizes glutamine metabolism and reduces nutrient
flexibility. Nat Commun. 8, 15074.
Shitara K., Doi T., Nagano O., Imamura C.K., Ozeki T., Ishii Y., Tsuchihashi K., Takahashi S.,
Nakajima T.E., Hironaka S., et al.,2017. Dose-escalation study for the targeting of CD44v+
cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205).
Gastric Cancer. 20, 341-349.
Singh D., Arora R., Kaur P., Singh B., Mannan R., Arora S.,2017. Overexpression of
hypoxia-inducible factor and metabolic pathways: possible targets of cancer. Cell Biosci. 7, 62.
Sinner D.I., Kim G.J., Henderson G.C., Igal R.A.,2012. StearoylCoA desaturase-5: a novel regulator
78
of neuronal cell proliferation and differentiation. PLoS One. 7, e39787.
Skouta R., Dixon S.J., Wang J., Dunn D.E., Orman M., Shimada K., Rosenberg P.A., Lo D.C.,
Weinberg J.M., Linkermann A., et al.,2014. Ferrostatins inhibit oxidative lipid damage and cell
death in diverse disease models. J. Am. Chem. Soc. 136, 4551–4556.
Smeyne M., Smeyne R.J.,2013. Glutathione metabolism and Parkinson's disease. Free Radic Biol Med.
62, 13-25.
Smolders V.F., Zodda E., Quax P.H.A., Carini M., Barberà J.A., Thomson T.M., Tura-Ceide O.,
Cascante M.,2019. Metabolic Alterations in Cardiopulmonary Vascular Dysfunction. Front Mol
Biosci. 5, 120.
Soga T., Heiger D.N.,2000. Amino acid analysis by capillary electrophoresis electrospray ionization mass spectrometry. Anal. Chem. 72, 1236–1241.
Soga T., Igarashi K., Ito C., Mizobuchi K., Zimmermann H.P., Tomita M.,2009. Metabolomic profiling of anionic metabolites by capillary electrophoresis mass spectrometry. Anal. Chem. 81,
6165–6174.
Soga T., Ohashi Y., Ueno Y., Naraoka H., Tomita M., Nishioka T.,2003. Quantitative metabolome analysis using capillary electrophoresis mass spectrometry. J. Proteome Res. 2, 488–494.
Soini Y., Karihtala P., Mäntyniemi A., Turunen N., Pääkkö P., Kinnula V.,2004. Glutamate-L-cysteine
ligase in breast carcinomas. Histopathology. 44, 129-135.
Strable M.S., Ntambi J.M.,2010. Genetic control of de novo lipogenesis: role in diet-induced obesity.
Crit Rev Biochem Mol Biol. 45, 199-214.
Sudhakaran S., Bottiglieri T., Tecson K.M., Kluger A.Y., McCullough P.A.,2018. Alteration of lipid
metabolism in chronic kidney disease, the role of novel antihyperlipidemic agents, and future
directions. Rev Cardiovasc Med. 19, 77-88.
Sun, Y., He, W., Luo, M., Zhou, Y., Chang, G., Ren, W., Wu, K., Li, X., Shen, J., Zhao, X., Hu,
Y.,2015. SREBP1 regulates tumorigenesis and prognosis of pancreatic cancer through targeting
lipid metabolism. Tumour Biol. 36, 4133–4141.
Sun J, Zhou C, Ma Q, Chen W, Atyah M, Yin Y, Fu P, Liu S, Hu B, Ren N, Zhou H.,2019. High GCLC
level in tumor tissues is associated with poor prognosis of hepatocellular carcinoma after curative
resection. J Cancer. 10, 3333-3343.
Tagde A., Singh H., Kang M.H., Reynolds C.P.,2014, The glutathione synthesis inhibitor buthionine
sulfoximine synergistically enhanced melphalan activity against preclinical models of multiple
myeloma. Blood Cancer J. 4, e229.
Tan, S.H., Shui, G., Zhou, J., Shi, Y., Huang, J., Xia, D., Wenk, M.R., Shen, HM.,2014. Critical role
of SCD1 in autophagy regulation via lipogenesis and lipid rafts-coupled AKT-FOXO1 signaling
pathway. Autophagy. 10, 226–242.
Tang Y., Zhou J., Hooi S.C., Jiang Y.M., Lu G.D.,2018. Fatty acid activation in carcinogenesis and
80
cancer development: Essential roles of long-chain acyl-CoA synthetases. Oncol Lett. 16,
1390-1396.
Terpstra M., Vaughan T.J., Ugurbil K., Lim K.O., Schulz S.C., Gruetter R.,2005. Validation of
glutathione quantitation from STEAM spectra against edited 1H NMR spectroscopy at 4T:
application to schizophrenia. MAGMA. 18, 276–282.
Theodoropoulos, P.C., Gonzales, S.S., Winterton, S.E., Rodriguez-Navas, C., McKnight, J.S.,
Morlock, L.K., Hanson, J.M., Cross, B., Owen, A.E., Duan, Y., et al.,2016. Discovery of
tumor-specific irreversible inhibitors of stearoyl CoA desaturase. Nat. Chem. Biol. 12, 218–225.
Tomanek L.,2015. Proteomic responses to environmentally induced oxidative stress. J Exp Biol. 218,
1867-1879.
Tracz-Gaszewska Z., Dobrzyn P.,2019. Stearoyl-CoA Desaturase 1 as a Therapeutic Target for the
Treatment of Cancer. Cancers (Basel). 11, 948.
Vander Heiden M.G., Cantley L.C., Thompson C.B.,2009. Understanding the Warburg effect: the
metabolic requirements of cell proliferation. Science. 324, 1029–1033.
Vargas, T., Moreno-Rubio, J., Herranz, J., Cejas, P., Molina, S., González-Vallinas, M., Mendiola,
M., Burgos, E., Aguayo, C., Custodio, A.B., et al.,2015. ColoLipidGene: signature of lipid
metabolism-related genes to predict prognosis in stage-II colon cancer patients. Oncotarget. 6,
7348–7363.
Viola H.M., Hool L.C.,2019. Impaired calcium handling and mitochondrial metabolic dysfunction as
early markers of hypertrophic cardiomyopathy. Arch Biochem Biophys. 665, 166-174.
von Roemeling, C.A., Marlow, L.A., Wei, J.J., Cooper, S.J., Caulfield, T.R., Wu, K., Tan, W.W., Tun,
H.W., Copland, J.A.,2013. Stearoyl-CoA desaturase 1 is a novel molecular therapeutic target for
clear cell renal cell carcinoma. Clin. Cancer. Res. 19, 2368–2380.
von Roemeling, C.A., Marlow, L.A., Pinkerton, A.B., Crist, A., Miller, J., Tun, H.W., Smallridge,
R.C., Copland, J.A.,2015. Aberrant lipid metabolism in anaplastic thyroid carcinoma reveals
stearoyl CoA desaturase 1 as a novel therapeutic target. J. Clin. Endocrinol. Metab. 100, E697–
709.
von Roemeling, C.A., Caulfield, T., Marlow, L., Bok, I., Wen, J., Miller, J., Hughes, R., Hazlehurst,
L., Pinkerton, A., Radisky, D., et al.,2017. Accelerated bottom-up drug design platform enables
the discovery of novel stearoyl-CoA desaturase 1 inhibitors for cancer therapy. Oncotarget. 9,
3–20.
Wang H., Wang L., Zhang H., Deng P., Chen J., Zhou B., Hu J., Zou J., Lu W., Xiang P., et al.,2013.
¹H NMR-based metabolic profiling of human rectal cancer tissue. Mol. Cancer. 12, 121.
Wang, J., Yu, L., Schmidt, R.E., Su, C., Huang, X., Gould, K., Cao, G.,2005. Characterization of
HSCD5, a novel human stearoyl-CoA desaturase unique to primates. Biochem. Biophys. Res.
Commun. 332, 735–742.
82
Wang, H., Zhang, Y., Lu, Y., Song, J., Huang, M., Zhang, J., Huang, Y.,2016. The role of
stearoyl-coenzyme A desaturase 1 in clear cell renal cell carcinoma. Tumour Biol. 37, 479–489.
Warburg, O.,1956. On the origin of cancer cells. Science. 123, 309–314.
Winkler B.S., DeSantis N., Solomon F.,1986. Multiple NADPH-producing pathways
control glutathione (GSH) content in retina. Exp. Eye. Res. 43, 829-847.
Winterbourn C.C., Brennan S.O.,1997. Characterization of the oxidation products of the reaction
between reduced glutathione and hypochlorous acid. Biochem. J. 326, 87-92.
Wolfgang M.J., Lane M.D.,2006. The role of hypothalamic malonyl-CoA in energy homeostasis. J
Biol Chem. 281, 37265-37269.
Xie Y., Hou W., Song X.,2016. Ferroptosis: process and function cell death and differentiation. 23,
369–379.
Yamada, T., Uchikata, T., Sakamoto, S., Yokoi, Y., Fukusaki, E., Bamba, T.S.,2013. Development of
a lipid profiling system using reverse-phase liquid chromatography coupled to high-resolution
mass spectrometry with rapid polarity switching and an automated lipid identification software.
J. Chromatogr. A. 1292, 211–218.
Yang W.S., SriRamaratnam R., Welsch M.E., Shimada K., Skouta R., Viswanathan V.S., Cheah J.H.,
Clemons P.A., Shamji A.F., Clish C.B., Brown L.M., et al.,2014. Regulation of ferroptotic
cancer cell death by GPX4. Cell. 156, 317–331.