4E-BP1 Is a Key Effector of the Oncogenic Activation of the AKT and ERK Signaling Pathways that Integrates Their Function in Tumors

被引：355

作者：

She, Qing-Bai ^{[1
]}

Halilovic, Ensar ^{[1
]}

Ye, Qing ^{[1
]}

Zhen, Wei ^{[1
]}

Shirasawa, Senji ^{[4
]}

Sasazuki, Takehiko ^{[5
]}

Solit, David B. ^{[2
,3
]}

Rosen, Neal ^{[1
,3
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol & Chem, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[4] Fukuoka Univ, Dept Cell Biol, Fukuoka 8140180, Japan

[5] Int Med Ctr Japan, Tokyo 1628655, Japan

来源：

CANCER CELL | 2010年 / 18卷 / 01期

关键词：

CAP-DEPENDENT TRANSLATION; HUMAN CANCER; COLORECTAL-CANCER; MEK INHIBITORS; CELL-GROWTH; TUBEROUS SCLEROSIS; KINASE PATHWAYS; PIK3CA GENE; IN-VIVO; PHOSPHORYLATION;

D O I：

10.1016/j.ccr.2010.05.023

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

PIK3CA and PTEN alterations are common in human cancer, but only a fraction of such tumors are dependent upon AKT signaling. AKT independence is associated with redundant activation of cap-dependent translation mediated by convergent regulation of the translational repressor 4E-BP1 by the AKT and ERK pathways. This provides mechanistic bases for the limited activity of AKT and MEK inhibitors in tumors with comutation of both pathways and the profound synergy observed with combined inhibition. Whereas such tumors are sensitive to a dominant active 4E-BP1 mutant, knockdown of 4E-BP1 expression reduces their dependence on AKT/ERK signaling for translation or survival. Thus, 4E-BP1 plays a prominent role in mediating the effects of these pathways in tumors in which they are activated by mutation.

引用

页码：39 / 51

页数：13

共 45 条

[1] 4E-Binding protein 1:: A key molecular "Funnel factor" in human cancer with clinical implications [J].

Armengol, Gemma ;

Rojo, Federico ;

Castellvi, Josep ;

Iglesias, Carmela ;

Cuatrecasas, Miriam ;

Pons, Berta ;

Baselga, Jose ;

Ramon y Cajal, Santiago .

CANCER RESEARCH, 2007, 67 (16) :7551-7555

[2] Activation of translation complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in human mammary epithelial cells [J].

Avdulov, S ;

Li, S ;

Michalek, V ;

Burrichter, D ;

Peterson, M ;

Perlman, DM ;

Manivel, JC ;

Sonenberg, N ;

Yee, D ;

Bitterman, PB ;

Polunovsky, VA .

CANCER CELL, 2004, 5 (06) :553-563

[3] The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901 [J].

Barrett, Stephen D. ;

Bridges, Alexander J. ;

Dudley, David T. ;

Saltiel, Alan R. ;

Fergus, James H. ;

Flamme, Cathlin M. ;

Delaney, Amy M. ;

Kaufman, Michael ;

LePage, Sophie ;

Leopold, Wilbur R. ;

Przybranowski, Sally A. ;

Sebolt-Leopold, Judith ;

Van Becelaere, Keri ;

Doherty, Annette M. ;

Kennedy, Robert M. ;

Marston, Dan ;

Howard, W. Allen, Jr. ;

Smith, Yvonne ;

Warmus, Joseph S. ;

Tecle, Haile .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (24) :6501-6504

[4] Allosteric inhibitors of Akt1 and Akt2: A naphthyridinone with efficacy in an A2780 tumor xenograft model [J].

Bilodeau, Mark T. ;

Balitza, Adrienne E. ;

Hoffman, Jacob M. ;

Manley, Peter J. ;

Barnett, Stanley F. ;

Defeo-Jones, Deborah ;

Haskell, Kathleen ;

Jones, Raymond E. ;

Leander, Karen ;

Robinson, Ronald G. ;

Smith, Anthony M. ;

Huber, Hans E. ;

Hartman, George D. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (11) :3178-3182

[5] The Mnks: MAP kinase-interacting kinases (MAP kinase signal-integrating kinases) [J].

Buxade, Maria ;

Parra-Palau, Josep L. ;

Proud, Christopher G. .

FRONTIERS IN BIOSCIENCE-LANDMARK, 2008, 13 :5359-5373

[6]

Carracedo A, 2008, J CLIN INVEST, V118, P3065, DOI [10.1172/JCI34739, 10.1172/jCI34739]

[7] An allosteric Akt inhibitor effectively blocks Akt signaling and tumor growth with only transient effects on glucose and insulin levels in vivo [J].

Cherrin, Craig ;

Haskell, Kathleen ;

Howell, Bonnie ;

Jones, Raymond ;

Leander, Karen ;

Robinson, Ronald ;

Watkins, Aubrey ;

Bilodeau, Mark ;

Hoffman, Jacob ;

Sanderson, Philip ;

Hartman, George ;

Mahan, Elizabeth ;

Prueksantanont, Thomayant ;

Jiang, Guoqiang ;

She, Qing-Bai ;

Rosen, Neal ;

Sepp-Lorenzino, Laura ;

Defeo-Jones, Deborah ;

Huber, Hans E. .

CANCER BIOLOGY & THERAPY, 2010, 9 (07) :493-503

[8] QUANTITATIVE-ANALYSIS OF DOSE-EFFECT RELATIONSHIPS - THE COMBINED EFFECTS OF MULTIPLE-DRUGS OR ENZYME-INHIBITORS [J].

CHOU, TC ;

TALALAY, P .

ADVANCES IN ENZYME REGULATION, 1984, 22 :27-55

[9] Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers [J].

Engelman, Jeffrey A. ;

Chen, Liang ;

Tan, Xiaohong ;

Crosby, Katherine ;

Guimaraes, Alexander R. ;

Upadhyay, Rabi ;

Maira, Michel ;

McNamara, Kate ;

Perera, Samanthi A. ;

Song, Youngchul ;

Chirieac, Lucian R. ;

Kaur, Ramneet ;

Lightbown, Angela ;

Simendinger, Jessica ;

Li, Timothy ;

Padera, Robert F. ;

Garcia-Echeverria, Carlos ;

Weissleder, Ralph ;

Mahmood, Umar ;

Cantley, Lewis C. ;

Wong, Kwok-Kin .

NATURE MEDICINE, 2008, 14 (12) :1351-1356

[10] Genetic inactivation of AKT1, AKT2, and PDPK1 in human colorectal cancer cells clarifies their roles in tumor growth regulation [J].

Ericson, Kajsa ;

Gan, Christine ;

Cheong, Ian ;

Rago, Carlo ;

Samuels, Yardena ;

Velculescu, Victor E. ;

Kinzler, Kenneth W. ;

Huso, David L. ;

Vogelstein, Bert ;

Papadopoulos, Nickolas .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (06) :2598-2603

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