Targeting Class IA PI3K Isoforms Selectively Impairs Cell Growth, Survival, and Migration in Glioblastoma
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Targeting Class IA PI3K Isoforms Selectively Impairs Cell Growth, Survival, and Migration in Glioblastoma. / Höland, Katrin; Boller, Danielle; Hagel, Christian; Dolski, Silvia; Treszl, András; Pardo, Olivier E; Cwiek, Paulina; Salm, Fabiana; Leni, Zaira; Shepherd, Peter R; Styp-Rekowska, Beata; Djonov, Valentin; von Bueren, André O; Frei, Karl; Arcaro, Alexandre.
in: PLOS ONE, Jahrgang 9, Nr. 4, 01.01.2014, S. e94132.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Targeting Class IA PI3K Isoforms Selectively Impairs Cell Growth, Survival, and Migration in Glioblastoma
AU - Höland, Katrin
AU - Boller, Danielle
AU - Hagel, Christian
AU - Dolski, Silvia
AU - Treszl, András
AU - Pardo, Olivier E
AU - Cwiek, Paulina
AU - Salm, Fabiana
AU - Leni, Zaira
AU - Shepherd, Peter R
AU - Styp-Rekowska, Beata
AU - Djonov, Valentin
AU - von Bueren, André O
AU - Frei, Karl
AU - Arcaro, Alexandre
PY - 2014/1/1
Y1 - 2014/1/1
N2 - The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is frequently activated in human cancer and plays a crucial role in glioblastoma biology. We were interested in gaining further insight into the potential of targeting PI3K isoforms as a novel anti-tumor approach in glioblastoma. Consistent expression of the PI3K catalytic isoform PI3K p110α was detected in a panel of glioblastoma patient samples. In contrast, PI3K p110β expression was only rarely detected in glioblastoma patient samples. The expression of a module comprising the epidermal growth factor receptor (EGFR)/PI3K p110α/phosphorylated ribosomal S6 protein (p-S6) was correlated with shorter patient survival. Inhibition of PI3K p110α activity impaired the anchorage-dependent growth of glioblastoma cells and induced tumor regression in vivo. Inhibition of PI3K p110α or PI3K p110β also led to impaired anchorage-independent growth, a decreased migratory capacity of glioblastoma cells, and reduced the activation of the Akt/mTOR pathway. These effects were selective, because targeting of PI3K p110δ did not result in a comparable impairment of glioblastoma tumorigenic properties. Together, our data reveal that drugs targeting PI3K p110α can reduce growth in a subset of glioblastoma tumors characterized by the expression of EGFR/PI3K p110α/p-S6.
AB - The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is frequently activated in human cancer and plays a crucial role in glioblastoma biology. We were interested in gaining further insight into the potential of targeting PI3K isoforms as a novel anti-tumor approach in glioblastoma. Consistent expression of the PI3K catalytic isoform PI3K p110α was detected in a panel of glioblastoma patient samples. In contrast, PI3K p110β expression was only rarely detected in glioblastoma patient samples. The expression of a module comprising the epidermal growth factor receptor (EGFR)/PI3K p110α/phosphorylated ribosomal S6 protein (p-S6) was correlated with shorter patient survival. Inhibition of PI3K p110α activity impaired the anchorage-dependent growth of glioblastoma cells and induced tumor regression in vivo. Inhibition of PI3K p110α or PI3K p110β also led to impaired anchorage-independent growth, a decreased migratory capacity of glioblastoma cells, and reduced the activation of the Akt/mTOR pathway. These effects were selective, because targeting of PI3K p110δ did not result in a comparable impairment of glioblastoma tumorigenic properties. Together, our data reveal that drugs targeting PI3K p110α can reduce growth in a subset of glioblastoma tumors characterized by the expression of EGFR/PI3K p110α/p-S6.
U2 - 10.1371/journal.pone.0094132
DO - 10.1371/journal.pone.0094132
M3 - SCORING: Journal article
C2 - 24718026
VL - 9
SP - e94132
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 4
ER -
