 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Apr 21, 2009 |
| Title |
Molecular pharmacology of phosphatidylinositol 3-kinase inhibition in human glioma |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
Gliomas are primary brain tumors with poor prognosis that
exhibit frequent abnormalities in phosphatidylinositol 3-kinase
(PI3 kinase) signaling. We investigated the molecular mechanism
of action of the isoform-selective class I PI3 kinase and mTOR
inhibitor PI-103 in human glioma cells. The potent inhibitory
effects of PI-103 on the PI3 kinase pathway were quantified.
PI-103 and the mTOR inhibitor rapamycin both inhibited ribosomal
protein S6 phosphorylation but there were clear differences
in the response of upstream components of the PI3 kinase pathway,
such as phosphorylation of Thr308-AKT, that were inhibited by
PI-103 but not rapamycin. Gene expression profiling identified
altered expression of genes encoding regulators of the cell cycle
and cholesterol metabolism, and genes modulated by insulin or
IGF1 signaling, rapamycin treatment or nutrient starvation. PI-103
decreased expression of positive regulators of G1/S phase progression
and increased expression of the negative cell cycle regulator
p27kip1. A reversible PI-103-mediated G1 cell cycle arrest occurred
without significant apoptosis, consistent with the altered gene
expression detected. PI-103 induced vacuolation and processing
of LC-3i to LC-3ii, which are features of an autophagic response.
In contrast to PI-103, LY294002 and PI-387 induced apoptosis,
indicative of likely off-target effects. PI-103 interacted synergistically
or additively with cytotoxic agents used in the treatment of
glioma, namely vincristine, BCNU and temozolomide. Compared
to individual treatments, the combination of PI-103 with temozolomide
significantly improved the response of U87MG human
glioma xenografts. Our results support the therapeutic potential
for PI3 kinase inhibitors with a PI-103-like profile as therapeutic
agents for the treatment of glioma.
Keywords: Key words: PI-103, glioma, PI3 kinase, mTOR, cell cycle, cytostasis
|
| |
|
| Overall design |
38 samples - All treated samples were compared to untreated parental cells
|
| |
|
| Contributor(s) |
Guillard S, Clarke P, te Poele R, Mohri Z, Bjerke L, Valenti M, Raynaud F, Eccles S, Workman P |
| Citation(s) |
19177002 |
| |
| Submission date |
Jul 21, 2008 |
| Last update date |
Apr 24, 2013 |
| Contact name |
Ian Giddings |
| E-mail(s) |
ian.giddings@icr.ac.uk, daniel.brewer@icr.ac.uk
|
| Phone |
+44 20 8722 4293
|
| Fax |
+44 20 8722 4141
|
| URL |
http://www.crukdmf.icr.ac.uk
|
| Organization name |
Institute of Cancer Research
|
| Department |
Section of Molecular Carcinogenesis
|
| Lab |
CANCER RESEARCH UK DNA Microarray Facility
|
| Street address |
15 Cotswold Road
|
| City |
Sutton |
| State/province |
Surrey |
| ZIP/Postal code |
SM2 5NG |
| Country |
United Kingdom |
| |
|
| Platforms (1) |
|
| Samples (38)
|
|
| Relations |
| BioProject |
PRJNA113469 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE12175_RAW.tar |
105.2 Mb |
(http)(custom) |
TAR (of GPR) |
| Processed data included within Sample table |
|
|
|
|
 |
Less...
More...