Basal Caspase Activity Promotes Migration and Invasiveness in Glioblastoma Cells

Abstract

Glioblastomas, the most malignant of all brain tumors, are characterized by cellular resistance to apoptosis and a highly invasive growth pattern. These factors contribute to the poor response of glioblastomas to radiochemotherapy and prevent their complete neurosurgical resection. However, the driving force behind the distinct motility of glioma cells is only partly understood. Here, we report that in the absence of cellular stress and proapoptotic stimuli, human glioblastoma cells exhibit a constitutive activation of caspases in vivo and in vitro. The inhibition of caspases by various peptide inhibitors decreases the migration of cells in scrape motility assays and the invasiveness of cells in spheroid assays. Similarly, specific small interfering RNA -or antisense-mediated down-regulation of caspase-3 and caspase-8 results in an inhibition of the migratory potential of glioma cells. The constitutive caspase-dependent motility of glioblastoma cells is independent of CD95 activation and it is not mediated by mitogen-activated protein/ extracellular signal-regulated kinase kinase signaling. The basal caspase activity is accompanied by a constant cleavage of the motility-associated gelsolin protein, which may contribute to the caspasemediated promotion of migration and invasiveness in glioblastoma cells. Our results suggest that the administration of low doses of caspase inhibitors that block glioma cell motility without affecting the execution of apoptotic cell death may be exploited as a novel strategy for the treatment of glioblastomas.

Immunohistochemical localization of caspase-3, caspase-9 and Bax in U87 glioblastoma xenografts

“…However, recent studies offer a new perspective on presence of caspases, mainly caspase-3, in the tumor cells (Yang et al 2003;Gdynia et al 2007). Gdynia et al (2007) reported that in the absence of cellular stress, active caspases are constitutively present in glioblastoma cells and promote their motility.…”

“…Gdynia et al (2007) reported that in the absence of cellular stress, active caspases are constitutively present in glioblastoma cells and promote their motility. Moderate active caspase-3 levels are found in human glioblastoma samples, freshly isolated glioblastoma cells, and long-term cultured glioma Immunoexpression of caspase-9 at 28 days after implantation.…”

New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy

“…Upon paclitaxel treatment, cancer cells with lower basal and weaker fold of induction of caspase-3 activity appeared to be more resilient to death compared to cells with higher basal and greater induction of caspase-3. Another study observed the basal activity of caspase-3 to promote invasiveness of glioma cells in the absence of death (Gdynia et al, 2007). These findings advocate that basal or low levels of caspase-3 are insufficient to engage the cell death pathways because of the failure to reach an effective threshold.…”

Spreading the word: non-autonomous effects of apoptosis during development, regeneration and disease

“…Thus, it might be counterintuitive that high levels of apoptosis are linked to poor prognosis in cancer (Jalalinadoushan et al, 2004;Leoncini et al, 1993;Nakopoulou et al, 2001;Naresh et al, 2001;Ohbu et al, 1995;Sun et al, 2006). The mechanism behind this unexpected observation is only now beginning to be understood: it has been shown that apoptotic signaling can drive tumor proliferation and invasion in different tumor models (Ballesteros-Arias et al, 2014;Gdynia et al, 2007;Liu et al, 2013;Maeda et al, 2005;Rudrapatna et al, 2013). Likewise, the treatment of tumors by chemotherapy or radiotherapy has recently been shown to induce tumor repopulation by increasing the release of PGE2 by apoptotic cells, which stimulates the growth of surviving tumor cells (Huang et al, 2011;Kurtova et al, 2014).…”