Spermine causes caspase activation in leukaemia cells

Abstract

Exposure of several leukaemia cell types to the polyamine spermine triggered caspase activation. In HL60 cells, the onset of caspase activity correlated with the accumulation of spermine, and was accompanied by the processing of the caspase-3 precursor and the digestion of the substrate proteins PARP and gelsolin. Spermine also induced the accumulation of cytochrome c in the cytosol. Caspase activation triggered by spermine was not blocked by antioxidants or inhibition of polyamine oxidase. The deregulation of polyamine uptake strongly sensitised the cells to spermine-induced caspase activation. These data show that an excessive intracellular level of spermine triggers caspase activation that is not mediated by oxidative mechanisms, and suggest a model where elevated free cytosolic polyamines may act as transducers of a death message.z 1998 Federation of European Biochemical Societies.

Perturbation of Polyamine Catabolism Can Strongly Affect Root Development and Xylem Differentiation

“…Consistent with the role of PAs as positive regulators of cell growth, these compounds protect cells from apoptosis and their overproduction has been linked to cell overproliferation and malignant development in animal cells (Wallace et al, 2003). On the other hand, either the increase or the decrease of physiological levels of PAs, induce the execution of the programmed cell death (PCD) syndrome (Seiler and Raul, 2005) either by caspase activation (Stefanelli et al, 1998) or cytochrome c release from mitocondria (Stefanelli et al, 2000), revealing PAs as bivalent regulators of cellular functions.…”

Polyamines directly induce release of cytochrome c from heart mitochondria

“…We have described here a cardiac cell-free model of apoptosis : caspase activity in cytosol of embryonal cardiomyocytes is triggered by the cytochrome c released from mitochondria by spermine. The described cell-free model can directly explain the toxicity of an excessively high level of intracellular spermine [11,44]. In fact, spermine and spermidine are present in high amounts within the cells, but are acknowledged to be almost totally bound to anionic structures, leaving only low concentrations of free polyamines [45].…”

“…Even if polyamines are necessary for growth processes, their excessive accumulation triggers apoptosis [7][8][9][10][11]. Activation of caspases represents a fundamental point in apoptosis [12] and mitochondria play a central role in this process [13], since the release of an apoptogenic factor, like cytochrome c, into the cytosol is a crucial step for caspase activation [14].…”

“…However, cytochrome c leakage in apoptotic cells is evident before mitochondria damage [18]. Spermine causes the leakage of cytochrome c into the cytosol both in whole cells [11] and in cell extracts containing mitochondria along with cytosol [19]. In order to study the mechanism of spermine action, we tested the hypothesis that spermine could directly affect the translocation of cytochrome c. The present paper reports that polyamines can Abbreviations used : CEHC, chick embryo heart cells ; CsA, cyclosporin A ; MIB, mitochondria incubation buffer ; MPT, mitochondrial permeability transition ; P/O ratio, ratio of ATP synthesized/O 2 consumed.…”

Transglutaminase activity during senescence and programmed cell death in the corolla of tobacco (Nicotiana tabacum) flowers

“…69 SM also caused cytochrome c exit from mitochondria and caspase activation in leukaemia cells and in a cell free system. 70,71 In these systems, a 2 ± 4-fold accumulation of free cytosolic PAs was responsible for the activation of the death programme. 69,71 In senescent Nicotiana corollas supplied with SM, free PAs increased to a similar extent; however, differently from animal cells, plants can buffer against excess PAs by conjugating them to low molecular weight molecules (TCA-soluble conjugates) and compartment them in the vacuole.…”