Targeting of mTORC2 prevents cell migration and promotes apoptosis in breast cancer

Breast Cancer Research and Treatment

Volumn 134, Issue 3, 2012, Pages 1057-1066

  Li, Haiyan ^a   Lin, Jun ^a   Wang, Xiaokai ^a   Yao, Guangyu ^a   Wang, Liping ^a,b   Zheng, Hang ^a   Yang, Cuilan ^a   Jia, Chunhong ^a   Liu, Anling ^a   Bai, Xiaochun ^a  

^a SOUTHERN MEDICAL UNIVERSITY   (China)

^b THE THIRD AFFILIATED HOSPITAL OF SOUTHERN MEDICAL UNIVERSITY   (China)

Author keywords

Apoptosis; Breast cancer; Mammalian target of rapamycin complex 2; Migration; MTOR kinase inhibitor; Rapamycin

Indexed keywords

2 (4 AMINO 1 ISOPROPYL 1H PYRAZOLO[3,4 D]PYRIMIDIN 3 YL) 1H INDOL 5 OL; 4 (4 AMINO 5 (7 METHOXY 1H INDOL 2 YL)IMIDAZO[5,1 F][1,2,4]TRIAZIN 7 YL)CYCLOHEXANECARBOXYLIC ACID; CISPLATIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; RAPAMYCIN;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BREAST CANCER; CANCER CELL CULTURE; CANCER CELL DESTRUCTION; CANCER INHIBITION; CELL MIGRATION; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG EFFICACY; DRUG POTENTIATION; DRUG USE; ENZYME INHIBITION; ENZYME PHOSPHORYLATION; FEMALE; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN TARGETING; SIGNAL TRANSDUCTION; TUMOR XENOGRAFT;

ANIMALS; APOPTOSIS; BREAST NEOPLASMS; CELL LINE, TUMOR; CELL MOVEMENT; CELL PROLIFERATION; CISPLATIN; FEMALE; HUMANS; IMIDAZOLES; INDOLES; MICE; PROTEIN KINASE INHIBITORS; PROTEINS; PURINES; SIGNAL TRANSDUCTION; TRANSCRIPTION FACTORS; TRIAZINES; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84868212354     PISSN: 01676806     EISSN: 15737217     Source Type: Journal    
DOI: 10.1007/s10549-012-2036-2     Document Type: Article

References (37)

1. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12(1):21-35
2. Guertin DA, Sabatini DM (2005) An expanding role for mTOR in cancer. Trends Mol Med 11(8):353-361
3. Laplante M, Sabatini DM (2009) mTOR signaling at a glance. J Cell Sci 122(Pt 20):3589-3594
4. Janes MR, Fruman DA (2010) Targeting TOR dependence in cancer. Oncotarget 1(1):69-76
5. Benjamin D, Colombi M, Moroni C, Hall MN (2011) Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov 10(11):868-880
6. Houghton PJ (2010) Everolimus. Clin Cancer Res 16(5):1368-1372
7. Guertin DA, Sabatini DM (2009) The pharmacology of mTOR inhibition. Sci Signal 2(67): pe24
8. Thoreen CC, Sabatini DM (2009) Rapamycin inhibits mTORC1, but not completely. Autophagy 5(5):725-726
9. Carew JS, Kelly KR, Nawrocki ST (2011) Mechanisms of mTOR inhibitor resistance in cancer therapy. Target Oncol 6(1):17-27
10. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, Shokat KM (2009) Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 7(2):e38
11. Yu K, Shi C, Toral-Barza L, Lucas J, Shor B, Kim JE, Zhang WG, Mahoney R, Gaydos C, Tardio L, Kim SK, Conant R, Curran K, Kaplan J, Verheijen J, Ayral-Kaloustian S, Mansour TS, Abraham RT, Zask A, Gibbons JJ (2010) Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. Cancer Res 70(2):621-631
12. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, Reichling LJ, Sim T, Sabatini DM, Gray NS (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284(12):8023-8032
13. Janes MR, Limon JJ, So L, Chen J, Lim RJ, Chavez MA, Vu C, Lilly MB, Mallya S, Ong ST, Konopleva M, Martin MB, Ren P, Liu Y, Rommel C, Fruman DA (2010) Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat Med 16(2):205-213
14. Shao H, Gao C, Tang H, Zhang H, Roberts LR, Hylander BL, Repasky EA, Ma WW, Qiu J, Adjei AA, Dy GK, Yu C (2012) Dual targeting of mTORC1/C2 complexes enhances histone deacetylase inhibitor-mediated anti-tumor efficacy in primary HCC cancer in vitro and in vivo. J Hepatol 56(1):176-183
15. Zhang YJ, Duan Y, Zheng XF (2011) Targeting the mTOR kinase domain: the second generation of mTOR inhibitors. Drug Discov Today 16 (7-8):325-331
16. Schenone S, Brullo C, Musumeci F, Radi M, Botta M (2011) ATP-competitive inhibitors of mTOR: an update. Curr Med Chem 18(20):2995-3014
17. Sparks CA, Guertin DA (2010) Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy. Oncogene 29(26):3733-3744
18. Bai X, Ma D, Liu A, Shen X, Wang QJ, Liu Y, Jiang Y (2007) Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science 318(5852):977-980
19. Li M, Zhao L, Liu J, Liu A, Jia C, Ma D, Jiang Y, Bai X (2010) Multi-mechanisms are involved in reactive oxygen species regulation of mTORC1 signaling. Cell Signal 22(10):1469-1476
20. Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27-55
21. Song G, Ouyang G, Bao S (2005) The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 9(1):59-71
22. Cohen SM, Lippard SJ (2001) Cisplatin: from DNA damage to cancer chemotherapy. Prog Nucleic Acid Res Mol Biol 67:93-130
23. Li DM, Feng YM (2011) Signaling mechanism of cell adhesion molecules in breast cancer metastasis: potential therapeutic targets. Breast Cancer Res Treat 128(1):7-21
24. Babcock JT, Quilliam LA (2011) Rheb/mTOR activation and regulation in cancer: novel treatment strategies beyond rapamycin. Curr Drug Targets 12(8):1223-1231
25. Brachmann SM, Hofmann I, Schnell C, Fritsch C, Wee S, Lane H, Wang S, Garcia-Echeverria C, Maira SM (2009) Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells. Proc Natl Acad Sci USA 106(52):22299-22304
26. Weigelt B, Warne PH, Downward J (2011) PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs. Oncogene 30(29):3222-3233
27. Wong SW, Tiong KH, Kong WY, Yue YC, Chua CH, Lim JY, Lee CY, Quah SI, Fow C, Chung C, So I, Tan BS, Choo HL, Rosli R, Cheong SK, Leong CO (2011) Rapamycin synergizes cisplatin sensitivity in basal-like breast cancer cells through upregulation of p73. Breast Cancer Res Treat 128(2):301-313
28. O'Regan R, Hawk NN (2011) mTOR inhibition in breast cancer: unraveling the complex mechanisms of mTOR signal transduction and its clinical implications in therapy. Expert Opin Ther Targets 15(7):859-872
29. Awada A, Cardoso F, Fontaine C, Dirix L, De Greve J, Sotiriou C, Steinseifer J, Wouters C, Tanaka C, Zoellner U, Tang P, Piccart M (2008) The oral mTOR inhibitor RAD001 (everolimus) in combination with letrozole in patients with advanced breast cancer: results of a phase I study with pharmacokinetics. Eur J Cancer 44(1):84-91
30. De Graffenried LA, Friedrichs WE, Russell DH, Donzis EJ, Middleton AK, Silva JM, Roth RA, Hidalgo M (2004) Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt Activity. Clin Cancer Res 10(23):8059-8067
31. Masri J, Bernath A, Martin J, Jo OD, Vartanian R, Funk A, Gera J (2007) mTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor. Cancer Res 67(24):11712-11720
32. Guertin DA, Stevens DM, Saitoh M, Kinkel S, Crosby K, Sheen JH, Mullholland DJ, Magnuson MA, Wu H, Sabatini DM (2009) mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell 15(2):148-159
33. Shorning BY, Griffiths D, Clarke AR (2011) Lkb1 and Pten synergise to suppress mTOR-mediated tumorigenesis and epithelial-mesenchymal transition in the mouse bladder. PLoS ONE 6(1):e16209
34. Gulhati P, Bowen KA, Liu J, Stevens PD, Rychahou PG, Chen M, Lee EY, Weiss HL, O'Connor KL, Gao T, Evers BM (2011) mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res 71(9):3246-3256
35. Inoki K, Mori H, Wang J, Suzuki T, Hong S, Yoshida S, Blattner SM, Ikenoue T, Ruegg MA, Hall MN, Kwiatkowski DJ, Rastaldi MP, Huber TB, Kretzler M, Holzman LB, Wiggins RC, Guan KL (2011) mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J Clin Invest 121(6):2181-2196
36. Zhang F, Zhang X, Li M, Chen P, Zhang B, Guo H, Cao W, Wei X, Cao X, Hao X, Zhang N (2010) mTOR complex component Rictor interacts with PKCzeta and regulates cancer cell metastasis. Cancer Res 70(22):9360-9370
37. Proud CG (2011) mTOR signalling in health and disease. Biochem Soc Trans 39(2):431-436