Abstract
The mammalian target of rapamycin (mTOR) signaling network regulates cell growth, proliferation and cell survival. Deregulated activation of this pathway is a common event in diverse human diseases such as cancers, cardiac hypertrophy, vascular restenosis and nephrotic hypertrophy. Although mTOR inhibitor, rapamycin, has been widely used to inhibit the aberrant signaling due to mTOR activation that plays a major role in hyperproliferative diseases, in some cases rapamycin does not attenuate the cell proliferation and survival. Thus, we studied the mechanism(s) by which cells may confer resistance to rapamycin. Our data show that in a variety of cell types the mTOR inhibitor rapamycin activates extracellularly regulated kinases (Erk1/2) signaling. Rapamycin-mediated activation of the Erk1/2 signaling requires (a) the epidermal growth factor receptor (EGFR), (b) its tyrosine kinase activity and (c) intact autophosphorylation sites on the receptor. Rapamycin treatment increases tyrosine phosphorylation of EGFR without the addition of growth factor and this transactivation of receptor involves activation of c-Src. We also show that rapamycin treatment triggers activation of cell survival signaling pathway by activating the prosurvival kinases Erk1/2 and p90RSK. These studies provide a novel paradigm by which cells escape the apoptotic actions of rapamycin and its derivatives that inhibit the mTOR pathway.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Abraham RT . (1998). Mammalian target of rapamycin: immunosuppressive drugs uncover a novel pathway of cytokine receptor signaling. Curr Opin Immunol 10: 330–336.
Arteaga CL, Ramsey TT, Shawver LK, Guyer CA . (1997). Unliganded epidermal growth factor receptor dimerization induced by direct interaction of quinazolines with the ATP binding site. J Biol Chem 272: 23247–23254.
Asakura M, Kitakaze M, Takashima S, Liao Y, Ishikura F, Yoshinaka T et al. (2002). Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy. Nat Med 8: 35–40.
Azzariti A, Porcelli L, Gatti G, Nicolin A, Paradiso A . (2008). Synergic antiproliferative and antiangiogenic effects of EGFR and mTOR inhibitors on pancreatic cancer cells. Biochem Pharmacol 75: 1035–1044.
Banko JL, Hou L, Poulin F, Sonenberg N, Klann E . (2006). Regulation of eukaryotic initiation factor 4E by converging signaling pathways during metabotropic glutamate receptor-dependent long-term depression. J Neurosci 26: 2167–2173.
Bjornsti MA, Houghton PJ . (2004). The TOR pathway: a target for cancer therapy. Nat Rev Cancer 4: 335–348.
Boluyt MO, Li ZB, Loyd AM, Scalia AF, Cirrincione GM, Jackson RR . (2004). The mTOR/p70S6K signal transduction pathway plays a role in cardiac hypertrophy and influences expression of myosin heavy chain genes in vivo. Cardiovasc Drugs Ther 18: 257–267.
Chaturvedi D, Poppleton HM, Stringfield T, Barbier A, Patel TB . (2006). Subcellular localization and biological actions of activated RSK1 are determined by its interactions with subunits of cyclic AMP-dependent protein kinase. Mol Cell Biol 26: 4586–4600.
Chen RH, Sarnecki C, Blenis J . (1992). Nuclear localization and regulation of Erk- and RSK-encoded protein kinases. Mol Cell Biol 12: 915–927.
Cohen MS, Zhang C, Shokat KM, Taunton J . (2005). Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Science 308: 1318–1321.
Costa LJ, Gemmill RM, Drabkin HA . (2007). Upstream signaling inhibition enhances rapamycin effect on growth of kidney cancer cells. Urology 69: 596–602.
Daub H, Wallasch C, Lankenau A, Herrlich A, Ullrich A . (1997). Signal characteristics of G protein-transactivated EGF receptor. EMBO J 16: 7032–7044.
Dormond O, Madsen JC, Briscoe DM . (2007). The effects of mTOR-AKT interactions on anti-apoptotic signaling in vascular endothelial cells. J Biol Chem 282: 23679–23686.
Dummler BA, Hauge C, Silber J, Yntema HG, Kruse LS, Kofoed B et al. (2005). Functional characterization of human RSK4, a new 90-kDa ribosomal S6 kinase, reveals constitutive activation in most cell types. J Biol Chem 280: 13304–13314.
Fischer OM, Hart S, Gschwind A, Ullrich A . (2003). EGFR signal transactivation in cancer cells. Biochem Soc Trans 31: 1203–1208.
Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA et al. (2006). mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 16: 1865–1870.
Frodin M, Gammeltoft S . (1999). Role and regulation of 90 kDa ribosomal S6 kinase (RSK) in signal transduction. Mol Cell Endocrinol 151: 65–77.
Fumarola C, La Monica S, Alfieri RR, Borra E, Guidotti GG . (2005). Cell size reduction induced by inhibition of the mTOR/S6K-signaling pathway protects Jurkat cells from apoptosis. Cell Death Differ 12: 1344–1357.
Galanis E, Buckner JC, Maurer MJ, Kreisberg JI, Ballman K, Boni J et al. (2005). Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 23: 5294–5304.
Goudar RK, Shi Q, Hjelmeland MD, Keir ST, McLendon RE, Wikstrand CJ et al. (2005). Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition. Mol Cancer Ther 4: 101–112.
Gschwind A, Hart S, Fischer OM, Ullrich A . (2003). TACE cleavage of proamphiregulin regulates GPCR-induced proliferation and motility of cancer cells. EMBO J 22: 2411–2421.
Guertin DA, Sabatini DM . (2005). An expanding role for mTOR in cancer. Trends Mol Med 11: 353–361.
Hardie DG, Hawley SA, Scott JW . (2006). AMP-activated protein kinase—development of the energy sensor concept. J Physiol 574: 7–15.
Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S, Rebholz H et al. (2004). The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 166: 213–223.
Huang S, Houghton PJ . (2003). Targeting mTOR signaling for cancer therapy. Curr Opin Pharmacol 3: 371–377.
Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X et al. (2006). TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126: 955–968.
Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY et al. (2006). SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127: 125–137.
Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A et al. (2004). Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6: 1122–1128.
Jin W, Yun C, Hobbie A, Martin MJ, Sorensen PH, Kim SJ . (2007). Cellular transformation and activation of the phosphoinositide-3-kinase-Akt cascade by the ETV6-NTRK3 chimeric tyrosine kinase requires c-Src. Cancer Res 67: 3192–3200.
Kiley SC, Chevalier RL . (2007). Species differences in renal Src activity direct EGF receptor regulation in life or death response to EGF. Am J Physiol Renal Physiol 293: F895–F903.
Kris M, Riely G, Azzoli C, Heelan R, Krug L, Pao W et al. (2007). Combined inhibition of mTOR and EGFR with everolimus (RAD001) and gefitinib in patients with non-small cell lung cancer who have smoked cigarettes: A phase II trial. J Clin Oncol 25: 18S.
Kudo N, Gillespie JG, Kung L, Witters LA, Schulz R, Clanachan AS et al. (1996). Characterization of 5′AMP-activated protein kinase activity in the heart and its role in inhibiting acetyl-CoA carboxylase during reperfusion following ischemia. Biochim Biophys Acta 1301: 67–75.
Li J, Lin ML, Wiepz GJ, Guadarrama AG, Bertics PJ . (1999). Integrin-mediated migration of murine B82L fibroblasts is dependent on the expression of an intact epidermal growth factor receptor. J Biol Chem 274: 11209–11219.
Lorenz MC, Heitman J . (1995). TOR mutations confer rapamycin resistance by preventing interaction with FKBP12-rapamycin. J Biol Chem 270: 27531–27537.
Manning BD . (2004). Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J Cell Biol 167: 399–403.
McMullen JR, Sherwood MC, Tarnavski O, Zhang L, Dorfman AL, Shioi T et al. (2004). Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation 109: 3050–3055.
Metro G, Finocchiaro G, Toschi L, Bartolini S, Magrini E, Cancellieri A et al. (2006). Epidermal growth factor receptor (EGFR) targeted therapies in non-small cell lung cancer (NSCLC). Rev Recent Clin Trials 1: 1–13.
Milton DT, Riely GJ, Azzoli CG, Gomez JE, Heelan RT, Kris MG et al. (2007). Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer. Cancer 110: 599–605.
Myers AP, Corson LB, Rossant J, Baker JC . (2004). Characterization of mouse Rsk4 as an inhibitor of fibroblast growth factor-RAS-extracellular signal-regulated kinase signaling. Mol Cell Biol 24: 4255–4266.
O’Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D et al. (2006). mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66: 1500–1508.
Parry TJ, Brosius R, Thyagarajan R, Carter D, Argentieri D, Falotico R et al. (2005). Drug-eluting stents: sirolimus and paclitaxel differentially affect cultured cells and injured arteries. Eur J Pharmacol 524: 19–29.
Prenzel N, Zwick E, Daub H, Leserer M, Abraham R, Wallasch C et al. (1999). EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402: 884–888.
Roux PP, Richards SA, Blenis J . (2003). Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity. Mol Cell Biol 23: 4796–4804.
Roux PP, Shahbazian D, Vu H, Holz MK, Cohen MS, Taunton J et al. (2007). RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation. J Biol Chem 282: 14056–14064.
Sabatini DM . (2006). mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 6: 729–734.
Saito Y, Haendeler J, Hojo Y, Yamamoto K, Berk BC . (2001). Receptor heterodimerization: essential mechanism for platelet-derived growth factor-induced epidermal growth factor receptor transactivation. Mol Cell Biol 21: 6387–6394.
Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H et al. (2004). Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14: 1296–1302.
Sarbassov DD, Ali SM, Sabatini DM . (2005). Growing roles for the mTOR pathway. Curr Opin Cell Biol 17: 596–603.
Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF et al. (2006). Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22: 159–168.
Sharma S, Ying J, Razeghi P, Stepkowski S, Taegtmeyer H . (2006). Atrophic remodeling of the transplanted rat heart. Cardiology 105: 128–136.
Shimamura A, Ballif BA, Richards SA, Blenis J . (2000). Rsk1 mediates a MEK-MAP kinase cell survival signal. Curr Biol 10: 127–135.
Sun SY, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H et al. (2005). Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res 65: 7052–7058.
Tice DA, Biscardi JS, Nickles AL, Parsons SJ . (1999). Mechanism of biological synergy between cellular Src and epidermal growth factor receptor. Proc Natl Acad Sci USA 96: 1415–1420.
Tzatsos A, Kandror KV . (2006). Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. Mol Cell Biol 26: 63–76.
Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M et al. (2004). Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431: 200–205.
VanderWeele DJ, Zhou R, Rudin CM . (2004). Akt up-regulation increases resistance to microtubule-directed chemotherapeutic agents through mammalian target of rapamycin. Mol Cancer Ther 3: 1605–1613.
Vega F, Medeiros LJ, Leventaki V, Atwell C, Cho-Vega JH, Tian L et al. (2006). Activation of mammalian target of rapamycin signaling pathway contributes to tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Cancer Res 66: 6589–6597.
Vivanco I, Sawyers CL . (2002). The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2: 489–501.
Wan X, Harkavy B, Shen N, Grohar P, Helman LJ . (2007). Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 26: 1932–1940.
Wendel HG, De Stanchina E, Fridman JS, Malina A, Ray S, Kogan S et al. (2004). Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428: 332–337.
Wullschleger S, Loewith R, Hall MN . (2006). TOR signaling in growth and metabolism. Cell 124: 471–484.
Acknowledgements
We are indebted to Dr PJ Bertics for providing us with the B82L cells, the EGFR cDNA and EGFR antibodies and to Ms Kuldeep Patel for the immunocytochemical analyses. This study was supported by American Heart Association-SDG AHA-ID-0830411Z (to DC) and NIH Grants GM071434 (to JT), GM 079226 and GM73181 (to TBP).
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)
Rights and permissions
About this article
Cite this article
Chaturvedi, D., Gao, X., Cohen, M. et al. Rapamycin induces transactivation of the EGFR and increases cell survival. Oncogene 28, 1187–1196 (2009). https://doi.org/10.1038/onc.2008.490
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2008.490
Keywords
This article is cited by
-
A phase I trial of temsirolimus and erlotinib in patients with refractory solid tumors
Cancer Chemotherapy and Pharmacology (2021)
-
The class I PI3K/Akt pathway is critical for cancer cell survival in dogs and offers an opportunity for therapeutic intervention
BMC Veterinary Research (2012)
-
PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer
Oncogene (2011)