Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition
The mammalian target of rapamycin (mTOR) has emerged as an important cancer therapeutic target. Rapamycin and its derivatives that specifically inhibit mTOR are now being actively evaluated in clinical trials. Recently, the inhibition of mTOR has been shown to reverse Akt-dependent prostate intraepi...
Uloženo v:
| Vydáno v: | Cancer research (Chicago, Ill.) Ročník 65; číslo 16; s. 7052 |
|---|---|
| Hlavní autoři: | , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
United States
15.08.2005
|
| Témata: | |
| ISSN: | 0008-5472 |
| On-line přístup: | Zjistit podrobnosti o přístupu |
| Tagy: |
Přidat tag
Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!
|
| Abstract | The mammalian target of rapamycin (mTOR) has emerged as an important cancer therapeutic target. Rapamycin and its derivatives that specifically inhibit mTOR are now being actively evaluated in clinical trials. Recently, the inhibition of mTOR has been shown to reverse Akt-dependent prostate intraepithelial neoplasia. However, many cancer cells are resistant to rapamycin and its derivatives. The mechanism of this resistance remains a subject of major therapeutic significance. Here we report that the inhibition of mTOR by rapamycin triggers the activation of two survival signaling pathways that may contribute to drug resistance. Treatment of human lung cancer cells with rapamycin suppressed the phosphorylation of p70S6 kinase and 4E-BP1, indicating an inhibition of mTOR signaling. Paradoxically, rapamycin also concurrently increased the phosphorylation of both Akt and eIF4E. The rapamycin-induced phosphorylation of Akt and eIF4E was suppressed by the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002, suggesting the requirement of PI3K in this process. The activated Akt and eIF4E seem to attenuate rapamycin's growth-inhibitory effects, serving as a negative feedback mechanism. In support of this model, rapamycin combined with LY294002 exhibited enhanced inhibitory effects on the growth and colony formation of cancer cells. Thus, our study provides a mechanistic basis for enhancing mTOR-targeted cancer therapy by combining an mTOR inhibitor with a PI3K or Akt inhibitor. |
|---|---|
| AbstractList | The mammalian target of rapamycin (mTOR) has emerged as an important cancer therapeutic target. Rapamycin and its derivatives that specifically inhibit mTOR are now being actively evaluated in clinical trials. Recently, the inhibition of mTOR has been shown to reverse Akt-dependent prostate intraepithelial neoplasia. However, many cancer cells are resistant to rapamycin and its derivatives. The mechanism of this resistance remains a subject of major therapeutic significance. Here we report that the inhibition of mTOR by rapamycin triggers the activation of two survival signaling pathways that may contribute to drug resistance. Treatment of human lung cancer cells with rapamycin suppressed the phosphorylation of p70S6 kinase and 4E-BP1, indicating an inhibition of mTOR signaling. Paradoxically, rapamycin also concurrently increased the phosphorylation of both Akt and eIF4E. The rapamycin-induced phosphorylation of Akt and eIF4E was suppressed by the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002, suggesting the requirement of PI3K in this process. The activated Akt and eIF4E seem to attenuate rapamycin's growth-inhibitory effects, serving as a negative feedback mechanism. In support of this model, rapamycin combined with LY294002 exhibited enhanced inhibitory effects on the growth and colony formation of cancer cells. Thus, our study provides a mechanistic basis for enhancing mTOR-targeted cancer therapy by combining an mTOR inhibitor with a PI3K or Akt inhibitor.The mammalian target of rapamycin (mTOR) has emerged as an important cancer therapeutic target. Rapamycin and its derivatives that specifically inhibit mTOR are now being actively evaluated in clinical trials. Recently, the inhibition of mTOR has been shown to reverse Akt-dependent prostate intraepithelial neoplasia. However, many cancer cells are resistant to rapamycin and its derivatives. The mechanism of this resistance remains a subject of major therapeutic significance. Here we report that the inhibition of mTOR by rapamycin triggers the activation of two survival signaling pathways that may contribute to drug resistance. Treatment of human lung cancer cells with rapamycin suppressed the phosphorylation of p70S6 kinase and 4E-BP1, indicating an inhibition of mTOR signaling. Paradoxically, rapamycin also concurrently increased the phosphorylation of both Akt and eIF4E. The rapamycin-induced phosphorylation of Akt and eIF4E was suppressed by the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002, suggesting the requirement of PI3K in this process. The activated Akt and eIF4E seem to attenuate rapamycin's growth-inhibitory effects, serving as a negative feedback mechanism. In support of this model, rapamycin combined with LY294002 exhibited enhanced inhibitory effects on the growth and colony formation of cancer cells. Thus, our study provides a mechanistic basis for enhancing mTOR-targeted cancer therapy by combining an mTOR inhibitor with a PI3K or Akt inhibitor. The mammalian target of rapamycin (mTOR) has emerged as an important cancer therapeutic target. Rapamycin and its derivatives that specifically inhibit mTOR are now being actively evaluated in clinical trials. Recently, the inhibition of mTOR has been shown to reverse Akt-dependent prostate intraepithelial neoplasia. However, many cancer cells are resistant to rapamycin and its derivatives. The mechanism of this resistance remains a subject of major therapeutic significance. Here we report that the inhibition of mTOR by rapamycin triggers the activation of two survival signaling pathways that may contribute to drug resistance. Treatment of human lung cancer cells with rapamycin suppressed the phosphorylation of p70S6 kinase and 4E-BP1, indicating an inhibition of mTOR signaling. Paradoxically, rapamycin also concurrently increased the phosphorylation of both Akt and eIF4E. The rapamycin-induced phosphorylation of Akt and eIF4E was suppressed by the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002, suggesting the requirement of PI3K in this process. The activated Akt and eIF4E seem to attenuate rapamycin's growth-inhibitory effects, serving as a negative feedback mechanism. In support of this model, rapamycin combined with LY294002 exhibited enhanced inhibitory effects on the growth and colony formation of cancer cells. Thus, our study provides a mechanistic basis for enhancing mTOR-targeted cancer therapy by combining an mTOR inhibitor with a PI3K or Akt inhibitor. |
| Author | Sun, Shi-Yong Rosenberg, Laura M Wang, Xuerong Zhou, Zhongmei Yue, Ping Khuri, Fadlo R Fu, Haian |
| Author_xml | – sequence: 1 givenname: Shi-Yong surname: Sun fullname: Sun, Shi-Yong email: shi-yong_sun@emoryhealthcare.org organization: Department of Hematology and Oncology and Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA. shi-yong_sun@emoryhealthcare.org – sequence: 2 givenname: Laura M surname: Rosenberg fullname: Rosenberg, Laura M – sequence: 3 givenname: Xuerong surname: Wang fullname: Wang, Xuerong – sequence: 4 givenname: Zhongmei surname: Zhou fullname: Zhou, Zhongmei – sequence: 5 givenname: Ping surname: Yue fullname: Yue, Ping – sequence: 6 givenname: Haian surname: Fu fullname: Fu, Haian – sequence: 7 givenname: Fadlo R surname: Khuri fullname: Khuri, Fadlo R |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/16103051$$D View this record in MEDLINE/PubMed |
| BookMark | eNo9kEtPwzAQhH0oog_4CSCfuKXYiV85VlVbKlXiAudo4zjUkDghdory70lF6Wk1u59mNDtHE9c4g9ADJUtKuXomhKiIMxkvNbiI8IikVE7Q7Lqforn3n6PklPBbNKWCkmQUM1StdLAnCLZxuCnx6itgcAU2-y3bYN93p_FY4RbC8QcGj_MBd9BCPWjrotoUFoIpcA11DZUFhwN0Hyacna4Ytu5oc3tOuEM3JVTe3F_mAr1vN2_rl-jwutuvV4dIs0SFKBUpY1RLyCmDVOdMkyKRqlRlKrQpSClSLVhKFIkFz6lMyiSXKpGJVkWsOI8X6OnPt-2a7974kNXWa1NV4EzT-0wopoiQZAQfL2Cfj22ytrM1dEP2_5_4FwdhaSc |
| CitedBy_id | crossref_primary_10_1172_JCI37539 crossref_primary_10_1016_j_canlet_2012_02_005 crossref_primary_10_1038_s41467_020_15546_9 crossref_primary_10_1186_s13020_017_0154_9 crossref_primary_10_1097_JTO_0b013e3181ec1531 crossref_primary_10_1158_1078_0432_CCR_12_0552 crossref_primary_10_1158_0008_5472_CAN_11_3747 crossref_primary_10_1002_cncr_23651 crossref_primary_10_1038_nrd1902 crossref_primary_10_1200_JCO_2007_11_4017 crossref_primary_10_2527_jas_2013_6427 crossref_primary_10_1093_carcin_bgn221 crossref_primary_10_1128_MCB_01032_06 crossref_primary_10_1158_1078_0432_CCR_10_2289 crossref_primary_10_1517_14728222_12_2_209 crossref_primary_10_3390_ph15070824 crossref_primary_10_1124_jpet_110_178400 crossref_primary_10_3892_ijo_2012_1745 crossref_primary_10_1016_j_urolonc_2009_11_009 crossref_primary_10_1038_s41388_020_1366_5 crossref_primary_10_3390_molecules191118414 crossref_primary_10_1371_journal_pone_0017449 crossref_primary_10_1016_j_nano_2014_09_003 crossref_primary_10_1016_j_chembiol_2020_11_010 crossref_primary_10_1158_0008_5472_CAN_19_0180 crossref_primary_10_1016_j_molcel_2015_05_031 crossref_primary_10_1186_s12885_021_07794_9 crossref_primary_10_1002_ijc_29887 crossref_primary_10_1038_sj_onc_1210918 crossref_primary_10_1002_glia_22566 crossref_primary_10_1016_j_biocel_2010_09_018 crossref_primary_10_1016_j_ctrv_2012_12_002 crossref_primary_10_1016_j_cytogfr_2017_04_005 crossref_primary_10_1101_gad_453107 crossref_primary_10_1158_0008_5472_CAN_07_2154 crossref_primary_10_1634_theoncologist_11_3_274 crossref_primary_10_1136_gutjnl_2018_316822 crossref_primary_10_1021_jm901427g crossref_primary_10_1002_prca_200800001 crossref_primary_10_3389_fphar_2018_00958 crossref_primary_10_1158_0008_5472_CAN_07_3241 crossref_primary_10_1158_0008_5472_CAN_07_5783 crossref_primary_10_1158_1078_0432_CCR_17_0042 crossref_primary_10_1158_0008_5472_CAN_05_2925 crossref_primary_10_1016_j_febslet_2013_06_045 crossref_primary_10_3892_or_2025_8865 crossref_primary_10_1158_1078_0432_CCR_19_2808 crossref_primary_10_1158_0008_5472_CAN_07_5428 crossref_primary_10_1371_journal_pone_0052363 crossref_primary_10_1158_0008_5472_CAN_19_3674 crossref_primary_10_1016_j_exphem_2022_09_006 crossref_primary_10_1186_s13058_019_1202_4 crossref_primary_10_3390_ijms251910835 crossref_primary_10_1155_2017_6501385 crossref_primary_10_1111_exd_13882 crossref_primary_10_3390_jmse11051040 crossref_primary_10_1186_s12967_021_02842_1 crossref_primary_10_1128_MCB_01525_14 crossref_primary_10_1007_s10549_014_3250_x crossref_primary_10_3892_ijo_2015_3194 crossref_primary_10_1158_0008_5472_CAN_07_6769 crossref_primary_10_1371_journal_pbio_1000121 crossref_primary_10_1038_aps_2015_19 crossref_primary_10_1007_BF03262236 crossref_primary_10_1016_j_semcdb_2016_01_025 crossref_primary_10_1002_cam4_742 crossref_primary_10_1016_j_intimp_2016_06_034 crossref_primary_10_1186_s12935_021_02397_7 crossref_primary_10_3892_or_2016_4799 crossref_primary_10_3390_ijms16023267 crossref_primary_10_3389_fonc_2021_669518 crossref_primary_10_1016_j_canlet_2012_11_013 crossref_primary_10_1016_j_cbi_2017_06_029 crossref_primary_10_3390_ijms21082967 crossref_primary_10_3390_biomedicines9121809 crossref_primary_10_1111_j_1349_7006_2007_00439_x crossref_primary_10_3390_molecules26092601 crossref_primary_10_1074_jbc_M112_374405 crossref_primary_10_1016_j_febslet_2008_08_005 crossref_primary_10_3389_fendo_2019_00660 crossref_primary_10_1101_gad_1690808 crossref_primary_10_15252_embj_2022111614 crossref_primary_10_1007_s10549_010_0763_9 crossref_primary_10_1136_jclinpath_2014_202560 crossref_primary_10_1038_labinvest_2013_98 crossref_primary_10_1093_neuonc_noq103 crossref_primary_10_1593_tlo_12241 crossref_primary_10_4161_15384101_2014_977096 crossref_primary_10_1016_j_canlet_2009_09_015 crossref_primary_10_1016_j_canlet_2006_11_008 crossref_primary_10_1038_sj_onc_1209951 crossref_primary_10_1016_j_molcel_2006_09_019 crossref_primary_10_1038_sj_onc_1210938 crossref_primary_10_1101_gad_263145_115 crossref_primary_10_1111_j_1365_2133_2008_08991_x crossref_primary_10_1517_13543784_2010_499121 crossref_primary_10_1016_j_bmcl_2013_01_019 crossref_primary_10_1186_s13024_021_00428_5 crossref_primary_10_1016_S1556_0864_15_31524_0 crossref_primary_10_1111_cns_12685 crossref_primary_10_1177_0976500X221114003 crossref_primary_10_1517_13543776_17_9_1077 crossref_primary_10_1517_13543784_2011_577065 crossref_primary_10_2165_11594740_000000000_00000 crossref_primary_10_1017_S1462399409001227 crossref_primary_10_3390_cancers17142410 crossref_primary_10_1016_j_apsb_2016_07_006 crossref_primary_10_1016_j_cbi_2020_109243 crossref_primary_10_1158_1078_0432_CCR_09_0816 crossref_primary_10_1158_0008_5472_CAN_04_4559 crossref_primary_10_1158_0008_5472_CAN_09_1751 crossref_primary_10_1021_jacs_4c11930 crossref_primary_10_4155_fmc_2017_0062 crossref_primary_10_1038_nrd2062 crossref_primary_10_1038_srep28945 crossref_primary_10_3390_cells10061363 crossref_primary_10_1007_s10637_018_0578_9 crossref_primary_10_1038_s41467_023_35789_6 crossref_primary_10_1002_jcp_22941 crossref_primary_10_1158_1078_0432_CCR_07_0760 crossref_primary_10_1038_s41598_025_09081_0 crossref_primary_10_1158_0008_5472_CAN_06_1344 crossref_primary_10_1158_0008_5472_CAN_11_1780 crossref_primary_10_1158_1541_7786_MCR_09_0409 crossref_primary_10_1186_s13045_015_0108_6 crossref_primary_10_1158_0008_5472_CAN_09_2951 crossref_primary_10_1111_j_1476_5381_2009_00369_x crossref_primary_10_1016_j_bcp_2019_113729 crossref_primary_10_1038_onc_2017_233 crossref_primary_10_1038_s41419_021_03588_w crossref_primary_10_1016_j_seizure_2020_01_011 crossref_primary_10_1080_01635581_2016_1145244 crossref_primary_10_1016_j_bcp_2016_07_005 crossref_primary_10_1007_s10549_017_4375_5 crossref_primary_10_1111_apm_12398 crossref_primary_10_3389_fonc_2020_611690 crossref_primary_10_1007_s12253_011_9365_z crossref_primary_10_1016_j_ejca_2010_06_117 crossref_primary_10_1158_0008_5472_CAN_08_3222 crossref_primary_10_3390_cancers13010119 crossref_primary_10_1002_mc_20628 crossref_primary_10_1016_j_yexcr_2014_04_012 crossref_primary_10_1158_1078_0432_CCR_06_2837 crossref_primary_10_1158_0008_5472_CAN_13_2946 crossref_primary_10_1074_jbc_RA118_006587 crossref_primary_10_4161_cc_11_5_19598 crossref_primary_10_1016_j_canlet_2007_01_026 crossref_primary_10_4161_cc_10_5_14829 crossref_primary_10_1007_s11427_024_2760_4 crossref_primary_10_1038_bjc_2013_505 crossref_primary_10_1002_cncr_24239 crossref_primary_10_1038_nri2546 crossref_primary_10_1158_1078_0432_CCR_06_0764 crossref_primary_10_1016_j_ajpath_2013_01_002 crossref_primary_10_1074_jbc_M113_463679 crossref_primary_10_1038_sj_onc_1209990 crossref_primary_10_1158_1541_7786_MCR_12_0679 crossref_primary_10_1158_0008_5472_CAN_05_2879 crossref_primary_10_1158_1078_0432_CCR_10_2334 crossref_primary_10_1016_j_taap_2017_07_006 crossref_primary_10_1038_sj_onc_1209992 crossref_primary_10_1093_carcin_bgv012 crossref_primary_10_1111_bjh_13984 crossref_primary_10_1016_j_bbadis_2016_11_013 crossref_primary_10_1107_S1600536812012548 crossref_primary_10_1007_s00432_014_1628_0 crossref_primary_10_1111_cas_13323 crossref_primary_10_1158_1078_0432_CCR_13_3172 crossref_primary_10_1111_jcmm_12583 crossref_primary_10_1016_j_bcp_2009_04_033 crossref_primary_10_1158_0008_5472_CAN_16_2356 crossref_primary_10_1016_j_canlet_2018_07_014 crossref_primary_10_1186_s12885_020_07193_6 crossref_primary_10_1186_s12918_016_0278_z crossref_primary_10_1016_j_sna_2024_116141 crossref_primary_10_1038_bjc_2014_534 crossref_primary_10_1111_j_1349_7006_2008_00891_x crossref_primary_10_1002_mc_22826 crossref_primary_10_1182_blood_2012_08_446096 crossref_primary_10_1097_01243894_200602000_00002 crossref_primary_10_1016_j_bbrc_2007_03_131 crossref_primary_10_2217_fon_13_178 crossref_primary_10_1021_jm501026z crossref_primary_10_1128_MCB_00305_08 crossref_primary_10_1158_1078_0432_CCR_08_3007 crossref_primary_10_1158_1940_6207_CAPR_10_0178 crossref_primary_10_1517_14728222_11_6_771 crossref_primary_10_1016_j_biocel_2016_12_007 crossref_primary_10_1016_j_ccr_2006_03_029 crossref_primary_10_1158_1541_7786_MCR_20_0262 crossref_primary_10_1158_1078_0432_CCR_09_0986 crossref_primary_10_1038_sj_bjc_6606019 crossref_primary_10_1016_j_lungcan_2010_03_006 crossref_primary_10_1074_jbc_M117_799593 crossref_primary_10_1002_jcb_28851 crossref_primary_10_1016_j_cellsig_2006_05_015 crossref_primary_10_1371_journal_pone_0154745 crossref_primary_10_1128_JVI_01092_09 crossref_primary_10_1158_1078_0432_CCR_06_2923 crossref_primary_10_1016_j_clgc_2014_08_007 crossref_primary_10_1182_blood_2008_02_137752 crossref_primary_10_1016_j_bbrc_2010_06_017 crossref_primary_10_1007_s11060_009_9950_0 crossref_primary_10_1371_journal_pone_0265465 crossref_primary_10_1517_14728222_10_6_877 crossref_primary_10_1111_bcp_12888 crossref_primary_10_3390_ijms20030755 crossref_primary_10_1007_s12311_015_0701_9 crossref_primary_10_1093_jnci_djv212 crossref_primary_10_1186_s12885_019_6038_x crossref_primary_10_1172_JCI123049 crossref_primary_10_1158_1078_0432_CCR_12_0351 crossref_primary_10_1158_0008_5472_CAN_05_2825 crossref_primary_10_1158_1078_0432_CCR_10_2882 crossref_primary_10_1007_s40487_017_0046_2 crossref_primary_10_1177_1535370213498976 crossref_primary_10_1586_17446651_3_2_207 crossref_primary_10_3389_fgene_2019_00235 crossref_primary_10_1007_s12026_008_8038_9 crossref_primary_10_1517_14728222_2012_677439 crossref_primary_10_3390_ph5111236 crossref_primary_10_1128_MCB_00760_07 crossref_primary_10_3390_cells8091010 crossref_primary_10_1074_jbc_M115_665133 crossref_primary_10_1016_j_intimp_2017_11_044 crossref_primary_10_1038_onc_2012_43 crossref_primary_10_1007_s00018_012_0998_1 crossref_primary_10_4161_cc_11_3_19096 crossref_primary_10_1002_jcb_26136 crossref_primary_10_1002_hed_21621 crossref_primary_10_1016_j_canlet_2022_216042 crossref_primary_10_1016_j_drup_2013_10_001 crossref_primary_10_3389_fphar_2016_00395 crossref_primary_10_1016_j_bmc_2006_03_041 crossref_primary_10_1002_jbmr_114 crossref_primary_10_1007_s11684_020_0812_7 crossref_primary_10_1080_15384101_2015_1087623 crossref_primary_10_1016_j_bbagrm_2014_10_003 crossref_primary_10_2217_fmb_2023_0097 crossref_primary_10_1093_annonc_mdt248 crossref_primary_10_1038_bjc_2013_810 crossref_primary_10_1172_JCI62279 crossref_primary_10_1016_j_critrevonc_2011_01_007 crossref_primary_10_1016_j_ebiom_2015_11_031 crossref_primary_10_1111_epi_12013 crossref_primary_10_3816_CBC_2010_s_016 crossref_primary_10_1021_acs_jmedchem_5c00783 crossref_primary_10_1517_14728222_12_9_1139 crossref_primary_10_1371_journal_pone_0129663 crossref_primary_10_1016_j_ajpath_2010_11_023 crossref_primary_10_1200_JCO_2008_18_9514 crossref_primary_10_1016_j_ctrv_2014_12_011 crossref_primary_10_1016_j_cbi_2015_08_006 crossref_primary_10_2353_ajpath_2006_051078 crossref_primary_10_3892_ol_2012_1069 crossref_primary_10_1002_jcp_31363 crossref_primary_10_1016_j_canlet_2021_10_019 crossref_primary_10_1158_0008_5472_CAN_07_6163 crossref_primary_10_1016_j_bmcl_2012_05_104 crossref_primary_10_1016_j_ctrv_2014_06_006 crossref_primary_10_1158_1940_6207_CAPR_12_0272_T crossref_primary_10_3402_pba_v6_31688 crossref_primary_10_1111_jpi_12461 crossref_primary_10_1097_CCO_0b013e328011beec crossref_primary_10_1016_j_ejca_2011_01_003 crossref_primary_10_3892_or_2017_5901 crossref_primary_10_1634_theoncologist_12_8_1007 crossref_primary_10_4161_auto_19048 crossref_primary_10_1007_s00432_011_1009_x crossref_primary_10_1016_j_semcancer_2012_06_004 crossref_primary_10_1016_j_tibs_2007_09_001 crossref_primary_10_1002_pros_21178 crossref_primary_10_1016_j_jcpa_2025_03_190 crossref_primary_10_1016_j_lfs_2017_05_010 crossref_primary_10_1007_s11010_025_05391_z crossref_primary_10_1007_s10549_011_1910_7 crossref_primary_10_3892_ijmm_2014_1882 crossref_primary_10_1038_onc_2008_398 crossref_primary_10_1128_MCB_01061_10 crossref_primary_10_1016_j_tips_2013_04_007 crossref_primary_10_1158_1078_0432_CCR_06_2798 crossref_primary_10_1016_S1470_2045_17_30688_5 crossref_primary_10_1107_S1600536812027547 crossref_primary_10_1182_blood_2009_03_209247 crossref_primary_10_1093_nar_gkx831 crossref_primary_10_1093_neuonc_not247 crossref_primary_10_1038_sj_onc_1210343 crossref_primary_10_2217_fon_10_2 crossref_primary_10_1097_01_JTO_0000391378_17179_8f crossref_primary_10_1016_j_canlet_2012_06_018 crossref_primary_10_1186_2045_824X_4_11 crossref_primary_10_1038_leu_2008_27 crossref_primary_10_1093_jnci_djw182 crossref_primary_10_1016_j_canlet_2013_01_041 crossref_primary_10_2217_cns_2015_0005 crossref_primary_10_1074_jbc_M113_492702 crossref_primary_10_3389_fphar_2022_1000377 crossref_primary_10_1016_j_blre_2017_11_006 crossref_primary_10_1111_j_1467_789X_2011_00917_x crossref_primary_10_1038_s41401_022_00862_1 crossref_primary_10_3892_or_2017_5849 crossref_primary_10_1634_theoncologist_2010_0402 crossref_primary_10_1038_nrd4505 crossref_primary_10_1007_s11523_007_0054_5 crossref_primary_10_18632_oncotarget_10858 crossref_primary_10_1128_AAC_02325_18 crossref_primary_10_1111_jcmm_14036 crossref_primary_10_1038_s41419_020_2382_7 crossref_primary_10_1158_0008_5472_CAN_21_3605 crossref_primary_10_3760_cma_j_issn_0366_6999_20122864 crossref_primary_10_1007_s12609_013_0122_z crossref_primary_10_3892_or_2014_3389 crossref_primary_10_3390_proteomes4020016 crossref_primary_10_1371_journal_pone_0113037 crossref_primary_10_1016_j_brainresbull_2008_03_005 crossref_primary_10_2217_14796694_3_6_639 crossref_primary_10_1038_s41416_020_0988_2 crossref_primary_10_1634_theoncologist_2007_0171 crossref_primary_10_1016_j_jpba_2021_114436 crossref_primary_10_1073_pnas_0809743105 crossref_primary_10_1158_1078_0432_CCR_12_1067 crossref_primary_10_14694_EdBook_AM_2013_33_e28 crossref_primary_10_1038_ejhg_2008_162 crossref_primary_10_1158_1078_0432_CCR_10_2621 crossref_primary_10_3109_10428194_2015_1026816 crossref_primary_10_1038_s41416_025_03035_z crossref_primary_10_1038_cgt_2012_39 crossref_primary_10_1038_jcbfm_2013_82 crossref_primary_10_1007_s00404_014_3377_3 crossref_primary_10_3390_cancers14112639 crossref_primary_10_1097_IGC_0000000000000091 crossref_primary_10_1158_1078_0432_CCR_14_1998 crossref_primary_10_1007_s10549_017_4199_3 crossref_primary_10_1016_j_molimm_2010_07_014 crossref_primary_10_1093_neuonc_nor050 crossref_primary_10_1517_14728222_11_8_1055 crossref_primary_10_1016_j_ccr_2007_04_021 crossref_primary_10_1158_0008_5472_CAN_08_1522 crossref_primary_10_2217_fon_12_49 crossref_primary_10_1002_ijc_25742 crossref_primary_10_1182_blood_2009_05_220889 crossref_primary_10_1016_j_bbamcr_2020_118877 crossref_primary_10_1016_j_bcp_2011_11_022 crossref_primary_10_1007_s11010_024_05168_w crossref_primary_10_3892_or_2013_2512 crossref_primary_10_1080_07391102_2016_1262279 crossref_primary_10_1158_2326_6066_CIR_14_0095 crossref_primary_10_3390_cancers11081169 crossref_primary_10_1097_CAD_0b013e3283067681 crossref_primary_10_1128_JVI_01884_14 crossref_primary_10_1038_nrc1974 crossref_primary_10_3109_10428194_2013_806800 crossref_primary_10_1038_nrclinonc_2011_71 crossref_primary_10_1158_1078_0432_CCR_08_2924 crossref_primary_10_3390_molecules26072029 crossref_primary_10_1158_1078_0432_CCR_19_2697 crossref_primary_10_1136_jitc_2022_004875 crossref_primary_10_1158_0008_5472_CAN_10_0384 crossref_primary_10_1517_13543784_15_10_1201 crossref_primary_10_1158_1078_0432_CCR_09_0365 crossref_primary_10_1002_cncr_26165 crossref_primary_10_1158_1078_0432_CCR_07_4306 crossref_primary_10_1016_j_jdermsci_2014_08_002 crossref_primary_10_1080_2162402X_2015_1005448 crossref_primary_10_1517_14728220903225008 crossref_primary_10_3390_ijms140815260 crossref_primary_10_1002_advs_202405818 crossref_primary_10_1016_j_lfs_2020_117816 crossref_primary_10_1111_bju_13415 crossref_primary_10_1111_pcmr_12007 crossref_primary_10_1097_CAD_0b013e3280cc2c6f crossref_primary_10_1158_1078_0432_CCR_16_2141 crossref_primary_10_1002_cncr_29422 crossref_primary_10_1002_cncr_29424 crossref_primary_10_1038_srep18800 crossref_primary_10_1016_j_mvr_2022_104397 crossref_primary_10_1016_S1556_0864_15_30399_3 crossref_primary_10_1038_jid_2014_552 crossref_primary_10_1371_journal_pone_0173854 crossref_primary_10_1016_j_imlet_2021_09_005 crossref_primary_10_1016_j_canlet_2012_05_003 crossref_primary_10_1371_journal_pone_0059597 crossref_primary_10_1007_s10637_019_00778_4 crossref_primary_10_1093_carcin_bgs156 crossref_primary_10_1016_j_drup_2007_11_003 crossref_primary_10_1016_j_ctrv_2013_02_005 crossref_primary_10_1016_j_ccell_2017_01_014 crossref_primary_10_1158_1078_0432_CCR_06_1992 crossref_primary_10_1016_j_ejphar_2022_175301 crossref_primary_10_1158_1078_0432_CCR_11_2123 crossref_primary_10_1517_14656566_2014_899582 crossref_primary_10_3390_cancers12010109 crossref_primary_10_3816_CLC_2008_n_049 crossref_primary_10_1038_nrd2871 crossref_primary_10_3390_molecules23010042 crossref_primary_10_1038_onc_2016_363 crossref_primary_10_1186_s12967_023_04103_9 crossref_primary_10_1038_s41598_022_09638_3 crossref_primary_10_1158_0008_5472_CAN_12_1578 crossref_primary_10_1158_0008_5472_CAN_12_2545 crossref_primary_10_2147_OTT_S241632 crossref_primary_10_1158_1940_6207_CAPR_11_0232 crossref_primary_10_1158_1541_7786_MCR_10_0526 crossref_primary_10_1158_1078_0432_CCR_12_0839 crossref_primary_10_1155_2015_402385 crossref_primary_10_1586_14737140_8_2_283 crossref_primary_10_1017_S1462399408000586 crossref_primary_10_1007_s40495_015_0032_z crossref_primary_10_1093_neuonc_nor226 crossref_primary_10_3390_ijms160921138 crossref_primary_10_1158_1078_0432_CCR_11_0796 crossref_primary_10_1016_j_canlet_2013_06_017 crossref_primary_10_1016_j_tranon_2014_11_001 crossref_primary_10_1038_aps_2010_150 crossref_primary_10_1016_j_ejphar_2013_12_005 crossref_primary_10_1038_onc_2014_146 crossref_primary_10_1002_ijc_25304 crossref_primary_10_1002_cncr_31685 crossref_primary_10_3390_cancers15030703 crossref_primary_10_1038_pcan_2011_24 crossref_primary_10_1080_13543784_2018_1417384 crossref_primary_10_1016_j_ceca_2007_09_002 crossref_primary_10_1016_j_molmed_2007_08_001 crossref_primary_10_1186_1471_2407_12_166 crossref_primary_10_1371_journal_pone_0013910 crossref_primary_10_1158_1940_6207_CAPR_08_0237 crossref_primary_10_1016_j_canlet_2014_12_029 crossref_primary_10_1007_s10549_014_3239_5 crossref_primary_10_1007_s00280_016_3033_7 crossref_primary_10_1158_1078_0432_CCR_15_3051 crossref_primary_10_1002_pros_20548 crossref_primary_10_1074_jbc_M115_672170 crossref_primary_10_3390_cancers16071336 crossref_primary_10_1016_j_neo_2018_04_003 crossref_primary_10_1074_jbc_M111_304626 crossref_primary_10_1136_gutjnl_2013_306202 crossref_primary_10_1097_PPO_0b013e3181c51c8e crossref_primary_10_1016_j_ctrv_2011_04_001 crossref_primary_10_1038_s41419_020_03108_2 crossref_primary_10_3389_fnmol_2014_00083 crossref_primary_10_1096_fj_07_9100com crossref_primary_10_1002_acn3_51009 crossref_primary_10_1016_j_hoc_2011_04_008 crossref_primary_10_1111_j_1582_4934_2008_00364_x crossref_primary_10_7124_bc_00017C crossref_primary_10_1158_0008_5472_CAN_12_1319 crossref_primary_10_1016_j_bmcl_2010_12_026 crossref_primary_10_1111_ejh_12436 crossref_primary_10_1038_s41380_020_00964_4 crossref_primary_10_1186_1479_5876_11_292 crossref_primary_10_1158_1078_0432_CCR_07_0717 crossref_primary_10_1016_j_bbamcr_2010_06_011 crossref_primary_10_1016_j_drudis_2011_02_008 crossref_primary_10_1007_s00280_018_3543_6 crossref_primary_10_1158_1078_0432_CCR_13_2769 crossref_primary_10_1159_000485381 crossref_primary_10_1186_1471_2407_11_375 crossref_primary_10_3390_biology12091202 crossref_primary_10_1186_s13229_019_0311_3 crossref_primary_10_1016_j_ebiom_2023_104594 crossref_primary_10_1038_nrd2381 crossref_primary_10_1158_1078_0432_CCR_08_0405 crossref_primary_10_1517_14728222_2012_684680 crossref_primary_10_2302_kjm_58_1 crossref_primary_10_1007_s11523_010_0154_5 crossref_primary_10_2217_fon_10_97 crossref_primary_10_1016_j_bbrc_2012_10_106 crossref_primary_10_2478_s11756_014_0428_y crossref_primary_10_1002_jor_23409 crossref_primary_10_1097_CAD_0000000000000354 crossref_primary_10_1038_sj_leu_2404471 crossref_primary_10_1016_j_bbamcr_2019_03_013 crossref_primary_10_1155_2014_845763 crossref_primary_10_3892_or_2015_4277 crossref_primary_10_1007_s10549_013_2528_8 crossref_primary_10_1016_j_canlet_2014_07_027 crossref_primary_10_1186_1756_8722_7_23 crossref_primary_10_4161_auto_7_2_14074 crossref_primary_10_1158_0008_5472_CAN_11_0838 crossref_primary_10_3390_cancers15051444 crossref_primary_10_1158_2159_8290_CD_11_0085 crossref_primary_10_3389_fonc_2023_1076855 crossref_primary_10_1016_j_critrevonc_2008_01_007 crossref_primary_10_1097_CCO_0000000000000014 crossref_primary_10_3816_CBC_2005_n_041 crossref_primary_10_1186_1746_6148_8_73 crossref_primary_10_1371_journal_pone_0020899 crossref_primary_10_1111_bph_13203 crossref_primary_10_1016_j_canlet_2018_05_025 crossref_primary_10_1053_j_seminoncol_2013_05_010 crossref_primary_10_1097_01243894_200609000_00031 crossref_primary_10_3390_ijms21041199 crossref_primary_10_1002_hep_22915 crossref_primary_10_1016_j_biocel_2007_05_008 crossref_primary_10_14694_EdBook_AM_2013_33_e395 crossref_primary_10_1038_oncsis_2017_86 crossref_primary_10_1586_eem_09_19 crossref_primary_10_1158_0008_5472_CAN_10_3253 crossref_primary_10_1016_j_clgc_2019_10_013 crossref_primary_10_1007_s11064_010_0142_2 crossref_primary_10_1038_onc_2008_247 crossref_primary_10_1371_journal_pgen_1005291 crossref_primary_10_1038_labinvest_2010_133 crossref_primary_10_1038_onc_2013_122 crossref_primary_10_1093_hmg_ddw097 crossref_primary_10_1016_j_mce_2009_10_016 crossref_primary_10_1038_s41388_019_0877_4 crossref_primary_10_1158_0008_5472_CAN_17_3107 crossref_primary_10_3892_etm_2011_293 crossref_primary_10_1002_jcb_24997 crossref_primary_10_1016_j_bcp_2007_11_018 crossref_primary_10_1186_bcr3604 crossref_primary_10_1371_journal_pone_0206309 crossref_primary_10_1111_imm_12996 crossref_primary_10_1016_j_ceb_2009_01_016 crossref_primary_10_1038_onc_2008_490 crossref_primary_10_1158_1078_0432_CCR_06_2570 crossref_primary_10_1634_theoncologist_2013_0437 crossref_primary_10_1038_nature04869 crossref_primary_10_1074_jbc_M112_445148 crossref_primary_10_1038_s41589_021_00813_7 crossref_primary_10_1177_12034754251355595 crossref_primary_10_1016_j_taap_2016_03_017 crossref_primary_10_3390_molecules28073157 crossref_primary_10_1158_0008_5472_CAN_07_5869 crossref_primary_10_1111_j_1349_7006_2011_01967_x crossref_primary_10_4161_cc_10_22_18124 crossref_primary_10_1200_JCO_2010_28_0198 crossref_primary_10_1016_j_jid_2021_02_754 crossref_primary_10_1002_med_21260 crossref_primary_10_1038_onc_2012_306 crossref_primary_10_1016_j_yexcr_2007_12_019 crossref_primary_10_1186_1476_4598_12_81 crossref_primary_10_7124_bc_000125 crossref_primary_10_1038_s41419_020_03153_x crossref_primary_10_1007_s10637_014_0177_3 crossref_primary_10_1158_0008_5472_CAN_07_1394 crossref_primary_10_1016_j_jss_2008_07_035 crossref_primary_10_1517_14728222_2014_937426 crossref_primary_10_1016_j_cellsig_2023_110742 crossref_primary_10_1038_mt_2014_27 crossref_primary_10_1080_15384101_2015_1046653 crossref_primary_10_1593_neo_07905 crossref_primary_10_1007_s10549_010_1207_2 crossref_primary_10_1164_rccm_200802_306OC |
| ContentType | Journal Article |
| DBID | CGR CUY CVF ECM EIF NPM 7X8 |
| DOI | 10.1158/0008-5472.can-05-0917 |
| DatabaseName | Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed MEDLINE - Academic |
| DatabaseTitle | MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) MEDLINE - Academic |
| DatabaseTitleList | MEDLINE - Academic MEDLINE |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database |
| DeliveryMethod | no_fulltext_linktorsrc |
| Discipline | Medicine |
| ExternalDocumentID | 16103051 |
| Genre | Research Support, U.S. Gov't, Non-P.H.S Research Support, U.S. Gov't, P.H.S Research Support, Non-U.S. Gov't Journal Article Research Support, N.I.H., Extramural |
| GrantInformation_xml | – fundername: NIGMS NIH HHS grantid: R01 GM53165 |
| GroupedDBID | --- -ET .55 .GJ 18M 29B 2WC 34G 39C 3O- 53G 5GY 5RE 5VS 6J9 8WZ A6W ABOCM ACGFO ACIWK ACPRK ACSVP ADBBV ADCOW AENEX AFFNX AFHIN AFOSN AFRAH AFUMD AI. ALMA_UNASSIGNED_HOLDINGS BAWUL BTFSW C1A CGR CS3 CUY CVF DIK DU5 EBS ECM EIF EJD F5P FRP GX1 H13 IH2 KQ8 L7B LSO MVM NPM OHT OK1 P0W P2P PQQKQ RCR RHF RHI RNS SJN TR2 UDS VH1 VXZ W2D W8F WH7 WHG WOQ X7M XJT YKV YZZ ZCG ZGI 7X8 AAFWJ AAJMC AETEA |
| ID | FETCH-LOGICAL-c438t-969441c7ab14a9cb4c0d378f8f96ced0f69c649080265b173f3b78373c8d28552 |
| IEDL.DBID | 7X8 |
| ISICitedReferencesCount | 711 |
| ISICitedReferencesURI | http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000231188600005&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| ISSN | 0008-5472 |
| IngestDate | Fri Sep 05 12:15:28 EDT 2025 Wed Feb 19 01:37:39 EST 2025 |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 16 |
| Language | English |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-c438t-969441c7ab14a9cb4c0d378f8f96ced0f69c649080265b173f3b78373c8d28552 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| PMID | 16103051 |
| PQID | 68480670 |
| PQPubID | 23479 |
| ParticipantIDs | proquest_miscellaneous_68480670 pubmed_primary_16103051 |
| PublicationCentury | 2000 |
| PublicationDate | 2005-08-15 |
| PublicationDateYYYYMMDD | 2005-08-15 |
| PublicationDate_xml | – month: 08 year: 2005 text: 2005-08-15 day: 15 |
| PublicationDecade | 2000 |
| PublicationPlace | United States |
| PublicationPlace_xml | – name: United States |
| PublicationTitle | Cancer research (Chicago, Ill.) |
| PublicationTitleAlternate | Cancer Res |
| PublicationYear | 2005 |
| SSID | ssj0005105 |
| Score | 2.4272902 |
| Snippet | The mammalian target of rapamycin (mTOR) has emerged as an important cancer therapeutic target. Rapamycin and its derivatives that specifically inhibit mTOR... |
| SourceID | proquest pubmed |
| SourceType | Aggregation Database Index Database |
| StartPage | 7052 |
| SubjectTerms | Antineoplastic Combined Chemotherapy Protocols - pharmacology Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - enzymology Carcinoma, Non-Small-Cell Lung - metabolism Cell Growth Processes - drug effects Cell Line, Tumor Chromones - administration & dosage Enzyme Activation Eukaryotic Initiation Factor-4E - metabolism Humans Lung Neoplasms - drug therapy Lung Neoplasms - enzymology Lung Neoplasms - metabolism Morpholines - administration & dosage Phosphatidylinositol 3-Kinases - metabolism Phosphorylation - drug effects Protein Kinase Inhibitors - pharmacology Protein Kinases - metabolism Protein-Serine-Threonine Kinases - metabolism Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-akt Ribosomal Protein S6 Kinases, 70-kDa - metabolism Signal Transduction - drug effects Sirolimus - administration & dosage Sirolimus - pharmacology TOR Serine-Threonine Kinases |
| Title | Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/16103051 https://www.proquest.com/docview/68480670 |
| Volume | 65 |
| WOSCitedRecordID | wos000231188600005&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| hasFullText | |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV1JSwMxFA7VinhxX-qag9fopMlMEhCklBYFW3pQ6a1MNiw602pbpf_eJJ2pF8GDDMxhSEJI3rx8L2_5ALikXCZxXNfIWw-IWpUiGRuMhLaRe4QUgevw-YF1u7zfF70KuClzYXxYZakTg6LWI-XvyK8TTrnPKbkdvyPPGeV9qwWBxgqoEgdkvEyz_k-t8LgIYPQO_piyepG_g2N-vfx21Wx0Q_iaKBjLfsWY4axpb_1vlttgs8CYsLEQih1QMfkuWO8UXvQ98NZQJakZHFnYeJ3CNNfQ3LdpC05mTnk48YOeq_grnU-gnENPk57NXW8UMk0cSoVZmmXhjgQugsn9SMtmcJi_DGWIBtsHT-3WY_MOFawLSFHCp0gkwkEkxVKJaSqUpCrShHHLrUiU0ZFNhEq8u9BZb7HEjFgimTNzieK6zt2-H4DVfJSbIwCx5YY6iCMjpqgmJMXaRG44zSwxmOEauChXceCk2rsq0tyMZpNBuY41cLjYiMF4UXxj4BCq11H4-M--J2Aj1Fn19WvjU1C17n82Z2BNfU6Hk4_zICzu3e11vgF_UsjN |
| linkProvider | ProQuest |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Activation+of+Akt+and+eIF4E+survival+pathways+by+rapamycin-mediated+mammalian+target+of+rapamycin+inhibition&rft.jtitle=Cancer+research+%28Chicago%2C+Ill.%29&rft.au=Sun%2C+Shi-Yong&rft.au=Rosenberg%2C+Laura+M&rft.au=Wang%2C+Xuerong&rft.au=Zhou%2C+Zhongmei&rft.date=2005-08-15&rft.issn=0008-5472&rft.volume=65&rft.issue=16&rft.spage=7052&rft_id=info:doi/10.1158%2F0008-5472.CAN-05-0917&rft.externalDBID=NO_FULL_TEXT |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0008-5472&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0008-5472&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0008-5472&client=summon |