PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells
By A. Bleau, D. Hambardzumyan, Tatsuya Ozawa, Elena I. Fomchenko, Jason T. Huse, C. Brennan, Eric C. Holland. Cell Stem Cell, 2009
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Summary In normal brain, the side population (SP) phenotype is generated by ABC transporter activity and identifies stem cell and endothelial cell sub-populations by dye exclusion. By drug efflux, the ABCG2 transporter provides chemoresistance in stem cells and contributes to the blood brain barrier (BBB) when active in endothelial cells. We investigated the SP phenotype of mouse and human gliomas. In glioma endothelial cells, ABC transporter function is impaired, corresponding to disruption of the BBB in these tumors. By contrast, the SP phenotype is increased in non-endothelial cells that form neurospheres and are highly tumorigenic. In this cell population, Akt, but not its downstream target mTOR, regulates ABCG2 activity, and loss of PTEN increases the SP. This Akt-induced ABCG2 activation results from its transport to the plasma membrane. Temozolomide, the standard treatment of gliomas, although not an ABCG2 substrate, increases the SP in glioma cells, especially in cells missing PTEN.
Subfields: Cancer Research, Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/0362d213e0aee214214f0505ffa070ce4e79ba10
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Citations in the corpus
- Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment (2018, background): “Interestingly, it has been demonstrated that the PI3K/ Akt pathway specifically regulates ABCG2 activity via its localization to the plasma membrane, and loss of PTEN promotes the SP phenotype of human glioma cancer stem-like cells [78].”
- MEF promotes stemness in the pathogenesis of gliomas (2012, positive): “Mouse primary brain neurospheres were isolated as previously described (Bleau et al., 2009) and plated at different concentrations (10, 5, and 1 cell/ml).”
- Tumour-initiating cells: challenges and opportunities for anticancer drug discovery (2009, background): “The PI3K–AKT pathway regulates ABCG2 activity in glioma-initiating cell”
- Cancer stem cells in glioblastoma (2015, background): “While this approach has identified a population of self-renewing cells in a mouse glioma model (Bleau et al. 2009), it has not been used successfully to enrich for self-renewing cells in human GBM (Broadley et al.”
- Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma (2010, background): “Using fluorescent Hoechst dye, which is also an ABCG2 substrate, stem cells can be effectively sorted by fluorescence-activated cell sorting (FACS) from brain tumours as a 'side population' (SP) that exhibits a lower level of fluorescence than their non-stem cell-like counterparts in the 'main popul”