The role of interleukin-6-STAT3 signalling in glioblastoma

Abstract

Glioblastoma is the most common type of malignant brain tumor among adults and is currently a non-curable disease due primarily to its highly invasive phenotype, and the lack of successful current therapies. Despite surgical resection and post-surgical treatment patients ultimately develop recurrence of the tumour. Several signalling molecules have been implicated in the development, progression and aggressiveness of glioblastoma. The present study reviewed the role of interleukin (IL)-6, a cytokine known to be important in activating several pro-oncogenic signaling pathways in glioblastoma. The current study particularly focused on the contribution of IL-6 in recurrent glioblastoma, with particular focus on glioblastoma stem cells and resistance to therapy.

Keywords: IL-6; STAT3; glioblastoma; therapeutics.

Figure 1.

STAT3 activation pathway. STAT3 is activated through the interaction of cytokines and growth factors. Growth factors have intrinsic kinase activity, whereas the receptors of ligands have associated JAK that, when phosphorylated, acts as a platform for un-phosphorylated STAT3 to become activated. Phosphorylated STAT3 dimers (not shown in figure for simplicity) translocates to the nucleus where it up-regulates a variety of genes that can contribute to tumourigenesis. The STAT3 pathway is negatively regulated by a number of ways. SOCS3 inhibits the phosphorylation of JAK proteins and PIAS3 inhibits dimerisation of STAT3 monomers. Phosphorylated STAT3 dimers are not shown for simplicity.

Figure 2.

TMZ is an alkylating agent that induces DNA methylation of guanine at the O⁶ position causing double-stranded DNA breaks and ultimately cell death. MGMT is a DNA-repair protein that counteracts the apoptotic effects of temozolomide by removing alkyl groups from the O⁶ position of guanine enhancing cell survival. Thus glioblastoma with high MGMT expression are commonly refractory to temozolomide while glioblastoma with silenced MGMT through epigenetic methylation of the MGMT promoter display greater sensitivity to temozolomide. TMZ, Temozolomide; MGMT, O6-methylguanine DNA methyltransferase.