PKC delta maintains phenotypes of tumor initiating cells through cytokine-mediated autocrine loop with positive feedback

Abstract

The existence of tumor initiating cells (TICs) has been emerged as a good therapeutic target for treatment of glioblastoma that is the most aggressive brain tumor with poor prognosis. However, the molecular mechanisms that regulate the phenotypes of TICs still remain obscure. In this study, we found that PKC delta, among PKC isoforms, is preferentially activated in TICs and acts as a critical regulator for the maintenance of TICs in glioblastoma. By modulating the expression levels or activity of PKC delta, we demonstrated that PKC delta promotes self-renewal and tumorigenic potentials of TICs. Importantly, we found that the activation of PKC delta persists in TICs through an autocrine loop with positive feedback that was driven by PKC delta/STAT3/IL-23/JAK signaling axis. Moreover, for phenotypes of TICs, we showed that PKC delta activates AKT signaling component by phosphorylation specifically on Ser473. Taken together, we proposed that TICs regulate their own population in glioblastoma through an autocrine loop with positive feedback that is driven by PKC delta-dependent secretion of cytokines.