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Blocking phosphoinositide 3-kinase activity in colorectal cancer cells reduces proliferation but does not increase apoptosis alone or in combination with cytotoxic drugs


Reference:

Martin-Fernandez, C., Bales, J., Hodgkinson, C., Welman, A., Welham, M. J., Dive, C. and Morrow, C. J., 2009. Blocking phosphoinositide 3-kinase activity in colorectal cancer cells reduces proliferation but does not increase apoptosis alone or in combination with cytotoxic drugs. Molecular Cancer Research, 7 (6), pp. 955-965.

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Official URL:

http://dx.doi.org/10.1158/1541-7786.mcr-08-0445

Abstract

In response to growth factors, class IA phosphoinositide 3-kinases (PI3K) phosphorylate phosphatidylinositol-4,5-bisphosphate, converting it to phosphatidylinositol-3,4,5-trisphosphate to activate protein kinase B/Akt. This is widely reported to promote tumorigenesis via increased cell survival, proliferation, migration, and invasion, and many tumor types, including colorectal cancer, exhibit increased PI3K signaling. To investigate the effect of inhibiting PI3K and as an alternative to the use of small molecular inhibitors of PI3K with varying degrees of selectivity, HT29 and HCT116 colorectal cancer cells bearing mutant PIK3CA were generated that could be induced with doxycycline to express synchronously a dominant negative subunit of PI3K, Δp85α. On induction, decreased levels of phosphorylated protein kinase B were detected, confirming PI3K signaling impairment. Induction of Δp85α in vitro reduced cell number via accumulation in G0-G1 phase of the cell cycle in the absence of increased apoptosis. These effects were recapitulated in vivo. HT29 cells expressing Δp85α and grown as tumor xenografts had a significantly slower growth rate on administration of doxycycline with reduced Ki67 staining without increased levels of apoptotic tissue biomarkers. Furthermore, in vitro Δp85α expression did not sensitize HT29 cells to oxaliplatin- or etoposide-induced apoptosis, irrespective of drug treatment schedule. Further analysis comparing isogenic HCT116 cells with and without mutation in PIK3CA showed no effect of the mutation in either proliferative or apoptotic response to PI3K inhibition. These data show in colorectal cancer cells that PI3K inhibition does not provoke apoptosis per se nor enhance oxaliplatin- or etoposide-induced cell death

Details

Item Type Articles
CreatorsMartin-Fernandez, C., Bales, J., Hodgkinson, C., Welman, A., Welham, M. J., Dive, C. and Morrow, C. J.
DOI10.1158/1541-7786.mcr-08-0445
DepartmentsFaculty of Science > Pharmacy & Pharmacology
RefereedYes
StatusPublished
ID Code14871

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