The role of the Bmi1-GSK3β pathway in glioblastoma

Malignant gliomas remain one of the deadliest of all cancers despite maximal
therapy. They present unique challenges to therapy with a median survival of 12 months.
Simultaneous activation of several growth promoting and anti-apoptotic pathways
represents the basis for the failure of monotherapies against this disease. In order to
efficiently block growth of glioblastoma (GBM) cells, we have applied several
combinatorial approaches. We have found that combination of histone deactylase
inhibitors along with the glycolytic inhibitor 2-deoxyglucose (2DG) efficiently induced
apoptosis in GBM cells. Furthermore, combination of the microtubule inhibitor
patupilone and AEE788 –an inhibitor of EGFR, which is frequently activated in gliomas,
induced apoptosis in GBM cells at doses that as single drugs were not effective. In GBM
and other cancers, subpopulations of tumor cells with stem cell properties that are
believed to constitute a tumor cell reservoir, have been identified. GBM cells frequently
express the progenitor cell markers Nestin and Sox2 and low levels of the differentiation
markers CNPase, GFAP and !-tubulin III. Bmi1 and Glycogen synthase kinase 3 (GSK3)
has been implicated in stem cell maintenance, but how Bmi1 regulates differentiation is
still unknown. We have identified a link between Bmi1 and GSK3 and showed that
blocking GSK3 may be instrumental to reduce the GBM cancer stem cell pool. We found
that the GSK3 inhibitors SB216763 as well as Lithium chloride depleted the cancer stem
cell population in GBM cells and induced tumor cell differentiation, irrespective of the
CD133 status. Cell proliferation and colony formation were markedly reduced in a dosedependent
manner.
Future work giving a deeper insight into the regulatory mechanisms of the
receptor tyrosine kinases and downstream effectors will help us to identify more specific
targets. Understanding the mechanisms why some targeted therapies work and others fail
will finally bring us to the level that efficient long-term treatment strategies can be
envisaged.