Targeting Protein Kinase C in Glioblastoma Treatment

Abstract

Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor and is associated with a poor prognosis. Despite the use of combined treatment approaches, recurrence is almost inevitable and survival longer than 14 or 15 months after diagnosis is low. It is therefore necessary to identify new therapeutic targets to fight GBM progression and recurrence. Some publications have pointed out the role of glioma stem cells (GSCs) as the origin of GBM. These cells, with characteristics of neural stem cells (NSC) present in physiological neurogenic niches, have been proposed as being responsible for the high resistance of GBM to current treatments such as temozolomide (TMZ). The protein Kinase C (PKC) family members play an essential role in transducing signals related with cell cycle entrance, differentiation and apoptosis in NSC and participate in distinct signaling cascades that determine NSC and GSC dynamics. Thus, PKC could be a suitable druggable target to treat recurrent GBM. Clinical trials have tested the efficacy of PKCβ inhibitors, and preclinical studies have focused on other PKC isozymes. Here, we discuss the idea that other PKC isozymes may also be involved in GBM progression and that the development of a new generation of effective drugs should consider the balance between the activation of different PKC subtypes.

Keywords: enzastaurin; epidermal growth factor receptor; glioblastoma; glioma stem cells; neural stem cells; neuregulin; neurogenesis; protein kinase C; temozolomide.

Figure 1

Markers of glioma stem cells, neural stem cells and their progeny. GFAP: glial fibrillary acidic protein; CD133: prominin 1; SOX2: sex determining region Y-box 2; NG2: neuron-glial antigen 2; GD3: GD3 ganglioside; PDGFRa: platelet derived growth factor receptor alpha; MAG: myelin associated glycoprotein; MBP: myelin basic protein; O4: surface antigen O4; GLAST: astrocytic glutamate transporter; EGFR: epidermal growth factor receptor; ASCL1: Achaete-scute complex homolog-1 (ASCL1), known as MASH1 in rodents; Tuj1: neuron-specific class III beta-tubulin; DLX2: distal-less homeobox 2; DCX: doublecortin; PSA-NCAM: polysyalated-neural cell adhesion molecule; NeuN: hexaribonucleotide binding protein-3; MAP2: microtubule associated protein 2.

Figure 2

Classification and structure of PKC isozymes. Regulatory domains (C1A, C1B and C2) and binding sites for regulatory molecules: diacylglycerol (DAG), Ca2+, and phosphatidyl Serine (PS), as well as the conserved catalytic domains (C3 and C4) are shown.

Figure 3

Effect of classical, novel and atypical protein kinase C (PKC) activation in glioblastoma (GBM) physiology. Figure highlights the effects of activating different PKC isozymes in GBM.

Figure 4

The selective activation of different PKC isozymes may lead to the release of different growth factors, which will differentially activate ErbB receptors with different cells functions. Activation of epidermal growth factor receptor (EGFR) by ligands released in an ADAM17-mediated manner stimulate intracellular pathways leading to cell proliferation, cell cycle entrance and GBM growth. The use of enzastaurin inhibits these pathways. In addition to this drug, activation of novel PKC isozymes may facilitate the ADAM17-mediated release of neuregulins, stimulating differentiation and inhibiting proliferation survival and growth.