Importance of PKCδ signaling in fractionated-radiation-induced expansion of glioma-initiating cells and resistance to cancer treatment

Abstract

SummaryBrain tumors frequently recur or progress as focal masses after treatment with ionizing radiation. However, the mechanisms underlying the repopulation of tumor cells after radiation have remained unclear. In this study, we show that cellular signaling from Abelson murine leukemia viral oncogene homolog (Abl) to protein kinase Cd (PKCd) is crucial for fractionated-radiation-induced expansion of gliomainitiating cell populations and acquisition of resistance to anticancer treatments. Treatment of human glioma cells with fractionated radiation increased Abl and PKCd activity, expanded the CD133-positive (CD133 + ) cell population that possesses tumor-initiating potential and induced expression of glioma stem cell markers and self-renewal-related proteins. Moreover, cells treated with fractionated radiation were resistant to anticancer treatments. Small interfering RNA (siRNA)-mediated knockdown of PKCd expression blocked fractionated-radiation-induced CD133 + cell expansion and suppressed expression of glioma stem cell markers and self-renewal-related proteins. It also suppressed resistance of glioma cells to anticancer treatments. Similarly, knockdown of Abl led to a decrease in CD133 + cell populations and restored chemotherapeutic sensitivity. It also attenuated fractionated-radiation-induced PKCd activation, suggesting that Abl acts upstream of PKCd. Collectively, these data indicate that fractionated radiation induces an increase in the glioma-initiating cell population, decreases cellular sensitivity to cancer treatment and implicates activation of Abl-PKCd signaling in both events. These findings provide insights that might prove pivotal in the context of ionising-radiation-based therapeutic interventions for brain tumors.

Protein Kinase C (PKC) Isozymes and Cancer

“…PKC -mediated ROS production has also been indicated to increase paraquat (1,1 -dimethyl-4,4 -bipyridinium)-induced glioma cell death [238]. In a recent study, however, activation of PKC in patient-derived glioma cells increased the fractionatedradiation-induced expansion of glioma-initiating cells and resistance to cancer treatment [239].…”

Targeting therapy-resistant cancer stem cells by hyperthermia

“…Since noncycling cells are generally less susceptible to radiation and chemotherapeutic DNA-damaging agents [63][64][65], quiescence may be an important contributor to CSC therapy resistance [3]. Paradoxically, eradication of the cycling tumour cells arrests disease progression but it can also stimulate proliferation of quiescent cells that evaded therapy, which can then repopulate the tumour [66][67][68].…”

Synergistic Activity of Plant Based Bioactives in Combating Cancer: An Overview.

“…It could cause a shift from asymmetric to symmetric division or a fast cycle of glioma stem cells. Secondly, cancer stem cells are more resistant to radiation than that of cancer cells [17][18][19]. Resistance of cancer stem cells is caused by their preferential activation of the DNA damage response [20].…”