Abstract
Loss of either TSC1 or TSC2 causes tuberous sclerosis complex (TSC) via activation of mTOR signaling pathway. The two prominent features of TSC are skin lesions including hypomelanic macules and benign tumors in multiple organs, whose molecular alterations are largely unknown. We report here that Xc− cystine/glutamate antiporter (xCT) was elevated in Tsc2−/− or Pten−/− cells, Tsc1 knockout mouse tissues and TSC2-deficient human kidney tumor. xCT was transcriptionally boosted by mTOR-mediated Oct1 signaling cascade. Augmented xCT led to reduction of eumelanin and elevation of pheomelanin in Tsc1 skin knockout mice through mTOR signaling pathway. Disruption of xCT suppressed the proliferation and tumorigenesis of Pten-null cells and Tsc2-null cells. mTOR hyperactive cells were more sensitive to inhibitors of mTOR or xCT. Combined inhibition of mTOR and xCT synergistically blocked the propagation and oncogenesis of mTOR hyperactive cells. Therefore, oncogenic mTOR activation of xCT is a key connection between aberrant melanin synthesis and tumorigenesis. We suggest that xCT is a novel therapeutic target for TSC and other aberrant mTOR-related diseases.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Betz C, Hall MN. Where is mTOR and what is it doing there? J Cell Biol. 2013;203:563–74.
Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149:274–93.
Cully M, You H, Levine AJ, Mak TW. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer. 2006;6:184–92.
Thomas GV. mTOR and cancer: reason for dancing at the crossroads? Curr Opin Genet Dev. 2006;16:78–84.
Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–74.
Yang Q, Guan KL. Expanding mTOR signaling. Cell Res. 2007;17:666–81.
Ma J, Meng Y, Kwiatkowski DJ, Chen X, Peng H, Sun Q, et al. Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade. J Clin Invest. 2010;120:103–14.
Sun Q, Chen X, Ma J, Peng H, Wang F, Zha X, et al. Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc Natl Acad Sci USA. 2011;108:4129–34.
Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2000;103:211–25.
Kwiatkowski DJ, Zhang H, Bandura JL, Heiberger KM, Glogauer M, el-Hashemite N, et al. A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum Mol Genet. 2002;11:525–34.
Zhang H, Cicchetti G, Onda H, Koon HB, Asrican K, Bajraszewski N, et al. Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. J Clin Invest. 2003;112:1223–33.
Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell. 2005;8:179–83.
Samuels Y, Ericson K. Oncogenic PI3K and its role in cancer. Curr Opin Oncol. 2006;18:77–82.
Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6:729–34.
Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007;12:9–22.
Onda H, Lueck A, Marks PW, Warren HB, Kwiatkowski DJ. Tsc2(+/−) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background. J Clin Invest. 1999;104:687–95.
Kobayashi T, Minowa O, Kuno J, Mitani H, Hino O, Noda T. Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice. Cancer Res. 1999;59:1206–11.
Kwiatkowski DJ, Short MP. Tuberous sclerosis. Arch Dermatol. 1994;130:348–54.
Jozwiak S, Kawalec W, Dluzewska J, Daszkowska J, Mirkowicz-Malek M, Michalowicz R. Cardiac tumours in tuberous sclerosis: their incidence and course. Eur J Pediatr. 1994;153:155–7.
Jozwiak S, Gornicki J, Michalowicz R, Gastol P. A case of renal clear cell sarcoma in a child with tuberous sclerosis. Wiad Lek. 1993;46:846–8.
Short MP, Richardson EP Jr., Haines JL, Kwiatkowski DJ. Clinical, neuropathological and genetic aspects of the tuberous sclerosis complex. Brain Pathol. 1995;5:173–9.
Krueger DA, Northrup H. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49:255–65.
Northrup H, Krueger DA. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49:243–54.
Henske EP, Jozwiak S, Kingswood JC, Sampson JR, Thiele EA. Tuberous sclerosis complex. Nat Rev Dis Prim. 2016;2:16035.
Gold AP, Freeman JM. Depigmented nevi: the earliest sign of tuberous sclerosis. Pediatrics. 1965;35:1003–5.
Fitzpatrick TB, Szabo G, Hori Y, Simone AA, Reed WB, Greenberg MH. White leaf-shaped macules. Earliest visible sign of tuberous sclerosis. Arch Dermatol. 1968;98:1–6.
Desch LW. White forelock could be early sign of tuberous sclerosis. Arch Pediatr Adolesc Med. 1996;150:651–2.
Jozwiak S, Schwartz RA, Janniger CK, Michalowicz R, Chmielik J. Skin lesions in children with tuberous sclerosis complex: their prevalence, natural course, and diagnostic significance. Int J Dermatol. 1998;37:911–7.
Jozwiak S, Schwartz RA, Janniger CK, Bielicka-Cymerman J. Usefulness of diagnostic criteria of tuberous sclerosis complex in pediatric patients. J Child Neurol. 2000;15:652–9.
Nathan N, Wang JA, Li S, Cowen EW, Haughey M, Moss J, et al. Improvement of tuberous sclerosis complex (TSC) skin tumors during long-term treatment with oral sirolimus. J Am Acad Dermatol. 2015;73:802–8.
Teng JM, Cowen EW, Wataya-Kaneda M, Gosnell ES, Witman PM, Hebert AA, et al. Dermatologic and dental aspects of the 2012 International Tuberous Sclerosis Complex Consensus Statements. JAMA Dermatol. 2014;150:1095–101.
Fitzpatrick TB. History and significance of white macules, earliest visible sign of tuberous sclerosis. Ann N Y Acad Sci. 1991;615:26–35.
Tilgen W. Ultrastructure of white leaf-shaped macules in tuberous sclerosis (author’s transl). Arch Dermatol Forsch. 1973;248:13–27.
d’Ischia M, Wakamatsu K, Napolitano A, Briganti S, Garcia-Borron JC, Kovacs D, et al. Melanins and melanogenesis: methods, standards, protocols. Pigment Cell Melanoma Res. 2013;26:616–33.
Ito S, Wakamatsu K, Ozeki H. Chemical analysis of melanins and its application to the study of the regulation of melanogenesis. Pigment Cell Res. 2000;13(Suppl 8):103–9.
Chintala S, Li W, Lamoreux ML, Ito S, Wakamatsu K, Sviderskaya EV, et al. Slc7a11 gene controls production of pheomelanin pigment and proliferation of cultured cells. Proc Natl Acad Sci USA. 2005;102:10964–9.
Bannai S. Exchange of cystine and glutamate across plasma membrane of human fibroblasts. J Biol Chem. 1986;261:2256–63.
Christensen HN. Role of amino acid transport and countertransport in nutrition and metabolism. Physiol Rev. 1990;70:43–77.
Bannai S, Ishii T. A novel function of glutamine in cell culture: utilization of glutamine for the uptake of cystine in human fibroblasts. J Cell Physiol. 1988;137:360–6.
Iglehart JK, York RM, Modest AP, Lazarus H, Livingston DM. Cystine requirement of continuous human lymphoid cell lines of normal and leukemic origin. J Biol Chem. 1977;252:7184–91.
Gout PW, Kang YJ, Buckley DJ, Bruchovsky N, Buckley AR. Increased cystine uptake capability associated with malignant progression of Nb2 lymphoma cells. Leukemia. 1997;11:1329–37.
Wakamatsu K, Ito S, Rees JL. The usefulness of 4-amino-3-hydroxyphenylalanine as a specific marker of pheomelanin. Pigment Cell Res. 2002;15:225–32.
Zhang H, Bajraszewski N, Wu E, Wang H, Moseman AP, Dabora SL, et al. PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. J Clin Invest. 2007;117:730–8.
Hu Z, Wang Y, Huang F, Chen R, Li C, Wang F, et al. Brain expressed X-linked 2 is pivotal for hyperactive mTOR-mediated tumorigenesis. J Biol Chem. 2015;290:25756–65.
El-Hashemite N, Zhang H, Walker V, Hoffmeister KM, Kwiatkowski DJ. Perturbed IFN-gamma-Jak-signal transducers and activators of transcription signaling in tuberous sclerosis mouse models: synergistic effects of rapamycin-IFN-gamma treatment. Cancer Res. 2004;64:3436–43.
Chen R, Duan J, Li L, Ma Q, Sun Q, Ma J, et al. mTOR promotes pituitary tumor development through activation of PTTG1. Oncogene. 2017;36:979–88.
Ito S, Wakamatsu K. An improved modification of permanganate oxidation of eumelanin that gives a constant yield of pyrrole-2,3,5-tricarboxylic acid. Pigment Cell Res. 1994;7:141–4.
Thody AJ, Higgins EM, Wakamatsu K, Ito S, Burchill SA, Marks JM. Pheomelanin as well as eumelanin is present in human epidermis. J Invest Dermatol. 1991;97:340–4.
Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL, Bonenfant D, et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell. 2002;10:457–68.
Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520:57–62.
Kim YC, Guan KL. mTOR: a pharmacologic target for autophagy regulation. J Clin Invest. 2015;125:25–32.
Lyons SA, Chung WJ, Weaver AK, Ogunrinu T, Sontheimer H. Autocrine glutamate signaling promotes glioma cell invasion. Cancer Res. 2007;67:9463–71.
Lo M, Ling V, Wang YZ, Gout PW. The xc-cystine/glutamate antiporter: a mediator of pancreatic cancer growth with a role in drug resistance. Br J Cancer. 2008;99:464–72.
Rosado JO, Salvador M, Bonatto D. Importance of the trans-sulfuration pathway in cancer prevention and promotion. Mol Cell Biochem. 2007;301:1–12.
Uren JR, Lazarus H. l-cyst(e)ine requirements of malignant cells and progress toward depletion therapy. Cancer Treat Rep. 1979;63:1073–9.
Gout PW, Buckley AR, Simms CR, Bruchovsky N. Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the x(c)-cystine transporter: a new action for an old drug. Leukemia. 2001;15:1633–40.
Timmerman LA, Holton T, Yuneva M, Louie RJ, Padro M, Daemen A, et al. Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target. Cancer Cell. 2013;24:450–65.
Cao J, Tyburczy ME, Moss J, Darling TN, Widlund HR, Kwiatkowski DJ. Tuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activation. J Clin Invest. 2017;127:349–64.
Wataya-Kaneda M, Tanaka M, Yang L, Yang F, Tsuruta D, Nakamura A, et al. Clinical and histologic analysis of the efficacy of topical rapamycin therapy against hypomelanotic macules in tuberous sclerosis complex. JAMA Dermatol. 2015;151:722–30.
Yang F, Yang L, Wataya-Kaneda M, Yoshimura T, Tanemura A, Katayama I. Uncoupling of ER/mitochondrial oxidative stress in mTORC1 hyperactivation-associated skin hypopigmentation. J Invest Dermatol. 2018;138:669–78.
Prota G. Progress in the chemistry of melanins and related metabolites. Med Res Rev. 1988;8:525–56.
Jara JR, Aroca P, Solano F, Martinez JH, Lozano JA. The role of sulfhydryl compounds in mammalian melanogenesis: the effect of cysteine and glutathione upon tyrosinase and the intermediates of the pathway. Biochim Biophys Acta. 1988;967:296–303.
Acknowledgments
The study was supported by National Basic Research Program of China 973 Program Grants (2015CB553802), National Key Research and Development Program of China (2016YFC0905101 and 2018YFA0506903), National Science and Technology Major Projects for Major New Drugs Innovation and Develop (2018ZX09711003-004-002), National Natural Science Foundation of China (81572463 and 81730078), Ministry of Education of China 111 Project B08007, the Chinese Academy of Medical Sciences Initiative for Innovative Medicine (2016-I2M-1-001 and 2016-I2M-1-002), and Tsinghua University Initiative Scientific Research Program (20161080086).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Edited by V. Stambolic
Supplementary information
Rights and permissions
About this article
Cite this article
Li, C., Chen, H., Lan, Z. et al. mTOR-dependent upregulation of xCT blocks melanin synthesis and promotes tumorigenesis. Cell Death Differ 26, 2015–2028 (2019). https://doi.org/10.1038/s41418-019-0274-0
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41418-019-0274-0
This article is cited by
-
Pifithrin-μ sensitizes mTOR-activated liver cancer to sorafenib treatment
Cell Death & Disease (2025)
-
Augmented ERO1α upon mTORC1 activation induces ferroptosis resistance and tumor progression via upregulation of SLC7A11
Journal of Experimental & Clinical Cancer Research (2024)
-
Comparative transcriptome analysis of skin color-associated genes in leopard coral grouper (Plectropomus leopardus)
BMC Genomics (2023)
-
Establishment of SLC7A11‐knockout mouse and its preliminary investigation in melanoma
In Vitro Cellular & Developmental Biology - Animal (2023)
-
Multi-omics data integration reveals the molecular network of dysregulation IQGAP2-mTOR promotes cell proliferation
Human Cell (2023)
