Contribution of caspase-independent pathway to apoptosis in malignant glioma induced by carbon ion beams

Abstract

High linear energy transfer (LET) carbon ion beam (CIB) is becoming the best tool for external radiotherapy of inoperable tumors because of its greater cell killing than conventional low LET gamma or X-rays. In the present study, whether the caspase-independent pathway exerts the important contribution in CIB-induced cell apoptosis was explored. Herein we showed, despite the absence of caspase activity using a pan caspase inhibitor Z-VAD-FMK, that apoptosis induced by high LET CIB were clearly observed in the glioma cells. Simultaneously, the increased 8-OHdG level, PARP-1 activity and AIF translocation occurred in response to CIB irradiation. Moreover, it was distinctly higher in the nuclear translocation frequency along with PARP-1 activation when the caspase protease cascade was suppressed in the irradiated glioma cells. Nuclear colocalization between PARP-1 and AIF as well as a positive association of the PARP-1 mRNA expression with AIF translocation frequency indicated that PARP-1 activation controlled the translocation of AIF to the nucleus. Our findings strongly demonstrated that caspase-independent cell apoptosis provided a prominent compensation in the glioma cell death involving the PARP-1/AIF signaling pathway at 24 h after CIB exposure, and likely triggered by oxidative damage to DNA. The knowledge on the molecular mechanism of AIF-mediated cell death may be very useful for the improvement of the therapeutic efficacy of malignant gliomas with heavy charged particles.

Bcl-xL activity influences outcome of the mitotic arrest

“…Whereas HeLa did not survive in these conditions and underwent DiM after caspase inhibition at the same time as without caspase inhibitor. The contradiction in the response of cells arrested in mitosis to Z-VAD(OH)-FMK treatment becomes now apparent, since for some cells MOMP alone is sufficient to induce caspase-independent apoptosis through leakage of Smac-Diablo, IAP and Endonuclease G ( Chipuk et al, 2006 ; Niikura et al, 2007 ; Zhang et al, 2017 ), while other cells can survive after MOMP for more than 48 h ( Lartigue et al, 2009 ).…”

Ameliorating mitochondrial dysfunction restores carbon ion-induced cognitive deficits via co-activation of NRF2 and PINK1 signaling pathway

“…Acquisition speed was set up to low speed and the highest resolution, an automated condition provided in Flowsight imaging flow cytometer (Amnis/Merck Millipore, Darmstadt, Germany) [52] . Approximately 5000 cells were acquired.…”

Role of Mitochondria in Radiation Responses: Epigenetic, Metabolic, and Signaling Impacts

“…Furthermore, after C-ion irradiation of human malignant glioma cells (at 2 Gy), Zhang et al, observed up-regulation of PARP and translocation of AIF translocation from mitochondria to the nucleus as well as induction of caspase-independent apoptosis accompanied by higher oxidative damage in mtDNA than in nDNA [ 382 ]. They suggested that heavy-ion (C-ion)-induced apoptotic pathways may be more activated by mtDNA damage (and/or by plasma membrane death receptors) than by nDNA damage.…”