PI3K Signaling in Glioma-Animal Models and Therapeutic Challenges

被引：103

作者：

Cheng, Christine K. ^{[1
]}

Fan, Qi-Wen

Weiss, William A.

机构：

[1] Univ Calif San Francisco, Dept Neurol, Brain Tumor Res Ctr, San Francisco, CA 94143 USA

来源：

BRAIN PATHOLOGY | 2009年 / 19卷 / 01期

关键词：

glioblastoma; PI3; kinase; kinase inhibitors; Akt; metabolism; apoptosis; combination therapy; GROWTH-FACTOR RECEPTOR; PHOSPHATIDYLINOSITOL KINASE-ACTIVITY; INCREASED INSULIN SENSITIVITY; PHOSPHOINOSITIDE; 3-KINASE; GLIOBLASTOMA-MULTIFORME; CATALYTIC SUBUNIT; MICE LACKING; ONCOGENIC TRANSFORMATION; EMBRYONIC LETHALITY; P110-ALPHA ISOFORM;

D O I：

10.1111/j.1750-3639.2008.00233.x

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

The PI3 kinase (PI3K) family plays a complex role in cell biology and metabolism. Signaling through the PI3Ks is frequently activated in many human cancers, including glioblastoma, because of gain-of-function mutations in PIK3CA or loss of PTEN. Experiments involving genetic mouse models and small molecule inhibitors have helped to elucidate the roles of the regulatory and catalytic subunits of PI3K in metabolism and cancer. Downstream of PI3K is Akt, a critical effector of growth, proliferation and survival. The suggested dependence of glioblastoma tumors on PI3K signaling implies that PI3K inhibitors should lead to effective killing of these cancer cells, but that has been shown not to be the case. The engagement of other survival pathways in response to PI3K inhibition prompts the need to develop combination therapies that promote cytotoxicity in cancer cells.

引用

页码：112 / 120

页数：9

共 72 条

[1]

ANDREWS S, 2007, SCI STKE, pCM2

[2] Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110α subunit of phosphoinositide 3-kinase [J].

Bi, L ;

Okabe, I ;

Bernard, DJ ;

Wynshaw-Boris, A ;

Nussbaum, RL .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (16) :10963-10968

[3] Early embryonic lethality in mice deficient in the p110β catalytic subunit of PI 3-kinase [J].

Bi, L ;

Okabe, I ;

Bernard, DJ ;

Nussbaum, RL .

MAMMALIAN GENOME, 2002, 13 (03) :169-172

[4] Inhibition of macroautophagy triggers apoptosis [J].

Boya, P ;

González-Polo, RA ;

Casares, N ;

Perfettini, JL ;

Dessen, P ;

Larochette, N ;

Métivier, D ;

Meley, D ;

Souquere, S ;

Yoshimori, T ;

Pierron, G ;

Codogno, P ;

Kroemer, G .

MOLECULAR AND CELLULAR BIOLOGY, 2005, 25 (03) :1025-1040

[5] Phosphoinositide 3-kinase catalytic subunit deletion and regulatory subunit deletion have opposite effects on insulin sensitivity in mice [J].

Brachmann, SM ;

Ueki, K ;

Engelman, JA ;

Kahn, RC ;

Cantley, LC .

MOLECULAR AND CELLULAR BIOLOGY, 2005, 25 (05) :1596-1607

[6] The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid β-oxidation [J].

Buzzai, M ;

Bauer, DE ;

Jones, RG ;

DeBerardinis, RJ ;

Hatzivassiliou, G ;

Elstrom, RL ;

Thompson, CB .

ONCOGENE, 2005, 24 (26) :4165-4173

[7]

CARPENTER CL, 1990, J BIOL CHEM, V265, P19704

[8] The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas [J].

Chakravarti, A ;

Zhai, G ;

Suzuki, Y ;

Sarkesh, S ;

Black, PM ;

Muzikansky, A ;

Loeffler, JS .

JOURNAL OF CLINICAL ONCOLOGY, 2004, 22 (10) :1926-1933

[9] Characterization of structurally distinct, isoform-selective phosphoinositide 3′-kinase inhibitors in combination with radiation in the treatment of glioblastoma [J].

Chen, Jack S. ;

Zhou, Linda J. ;

Entin-Meer, Michal ;

Yang, Xiaodong ;

Donker, Mila ;

Knight, Zachary A. ;

Weiss, William ;

Shokat, Kevan M. ;

Haas-Kogan, Daphne ;

Stokoe, David .

MOLECULAR CANCER THERAPEUTICS, 2008, 7 (04) :841-850

[10] Comprehensive genomic characterization defines human glioblastoma genes and core pathways [J].

Chin, L. ;

Meyerson, M. ;

Aldape, K. ;

Bigner, D. ;

Mikkelsen, T. ;

VandenBerg, S. ;

Kahn, A. ;

Penny, R. ;

Ferguson, M. L. ;

Gerhard, D. S. ;

Getz, G. ;

Brennan, C. ;

Taylor, B. S. ;

Winckler, W. ;

Park, P. ;

Ladanyi, M. ;

Hoadley, K. A. ;

Verhaak, R. G. W. ;

Hayes, D. N. ;

Spellman, Paul T. ;

Absher, D. ;

Weir, B. A. ;

Ding, L. ;

Wheeler, D. ;

Lawrence, M. S. ;

Cibulskis, K. ;

Mardis, E. ;

Zhang, Jinghui ;

Wilson, R. K. ;

Donehower, L. ;

Wheeler, D. A. ;

Purdom, E. ;

Wallis, J. ;

Laird, P. W. ;

Herman, J. G. ;

Schuebel, K. E. ;

Weisenberger, D. J. ;

Baylin, S. B. ;

Schultz, N. ;

Yao, Jun ;

Wiedemeyer, R. ;

Weinstein, J. ;

Sander, C. ;

Gibbs, R. A. ;

Gray, J. ;

Kucherlapati, R. ;

Lander, E. S. ;

Myers, R. M. ;

Perou, C. M. ;

McLendon, Roger .

NATURE, 2008, 455 (7216) :1061-1068

← 1 2 3 4 5 6 7 8 →