Abstract
N‐(1‐pyrenyl) maleimide (NPM) has been recently identified as a telomerase inhibitor in a cell‐free system and shown to display a great differential cytotoxicity against hematopoietic cancer cells. However, the primary cytotoxic effect of NPM against hematopoietic cancer cells is induction of apoptosis, rather than inhibition of telomerase. In this study, the molecular mechanism by which NPM induces apoptosis was examined. Here, we show that treatment of Jurkat cells with NPM leads to Bak oligomerization, loss of mitochondrial membrane potential (Δψm), and release of cytochrome C from mitochondria to cytosol. Induction of Bak oligomerization appears to play a critical role in NPM‐induced apoptosis, as down‐regulation of Bak by shRNA significantly prevented NPM‐induced apoptosis in Jurkat cells. Inhibition of caspase‐8 by Z‐IETD‐FMK and/or depletion of Bid did not affect NPM‐induced oligomerization of Bak. Taken together, these results suggest that NPM‐induced apoptosis is mediated through induction of Bak oligomerization and mitochondrial dysfunction by a pathway that is independent of caspase‐8 activation.
Highlights
Apoptosis, the programmed cell death type I, plays an important role in developmental processes, maintenance ofE homeostasis, and elimination of damaged cells
The induction of apoptotic release of cytochrome C is regulated by anti- and proapop- cell death represents the mechanism of action for many totic Bcl-2 family of proteins, which reside in the outer anticancer drugs
E Because loss of Δψm is often associated with the release of mitochondrial intermembrane space proteins into the cytosol, we investigated whether cytochrome C is released from the N-(1-pyrenyl) maleimide (NPM)-treated cells
Summary
The programmed cell death type I, plays an important role in developmental processes, maintenance of. The induction of apoptotic release of cytochrome C is regulated by anti- and proapop- cell death represents the mechanism of action for many totic Bcl-2 family of proteins, which reside in the outer anticancer drugs. The ratio of proapoptotic to used in cancer therapy appear to exert their cytotoxic action antiapoptotic BCL-2 family proteins is a critical determinant through apoptosis induction (reviewed in [8]). Oligomerized Bax and/or Bak results in destabilization of the pyrenyl) maleimide (NPM) [13], that selectively inhibit mitochondrial outer membrane and subsequent release of telomerase in a cell-free system. Through inhibition of telomerase and potentially modulation of uncharacterized targets, the primary cytotoxic effect of NPM against hematopoietic cancer cells manifests by induction of apoptosis [13].
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