Abstract
Avicins, a family of plant triterpene electrophiles, can trigger apoptosis-associated tumor cell death, and suppress chemical-induced carcinogenesis by its anti-inflammatory, anti-mutagenic, and antioxidant properties. Here, we show that tumor cells treated with benzyloxycarbonylvalyl-alanyl-aspartic acid (O-methyl)-fluoro-methylketone, an apoptosis inhibitor, and Bax(-/-)Bak(-/-) apoptosis-resistant cells can still undergo cell death in response to avicin D treatment. We demonstrate that this non-apoptotic cell death is mediated by autophagy, which can be suppressed by chloroquine, an autophagy inhibitor, and by specific knockdown of autophagy-related gene-5 (Atg5) and Atg7. Avicin D decreases cellular ATP levels, stimulates the activation of AMP-activated protein kinase (AMPK), and inhibits mammalian target of rapamycin (mTOR) and S6 kinase activity. Suppression of AMPK by compound C and dominant-negative AMPK decreases avicin D-induced autophagic cell death. Furthermore, avicin D-induced autophagic cell death can be abrogated by knockdown of tuberous sclerosis complex 2 (TSC2), a key mediator linking AMPK to mTOR inhibition, suggesting that AMPK activation is a crucial event targeted by avicin D. These findings indicate the therapeutic potential of avicins by triggering autophagic cell death.
Highlights
Inhibitors, and HDAC inhibitors as well as irradiation all induce autophagic cell death in malignant cells.14These findings suggest that induction of autophagic cell death may provide an alternative therapeutic mechanism, in particular in apoptosis-resistant tumor cells
The cells treated with avicin D in the presence of zVAD–fmk for up to 48 h still underwent cell death (Figure 1c and d) the extent of cell death in zVAD–fmk-treated cells was less than that observed in the cells treated with avicin D alone (Figure 1c)
We demonstrated that avicin D induced a caspase-independent autophagic cell death, which could be suppressed by CQ and knockdown of Atg[5] and Atg[7]
Summary
Inhibitors, and HDAC inhibitors as well as irradiation all induce autophagic cell death in malignant cells.14These findings suggest that induction of autophagic cell death may provide an alternative therapeutic mechanism, in particular in apoptosis-resistant tumor cells. We recently discovered a family of plant triterpene electrophiles, avicins (Supplementary Figure 1), selectively inhibit growth in a wide variety of tumor cells.[15,16,17] Avicins activate the intrinsic caspase pathway to induce apoptosis by direct perturbation of mitochondria and by downregulation of Bcl[2] family prosurvival, antiapoptotic proteins that function downstream of cytochrome c release from mitochondria.[15,16,17,18] In addition to the cytotoxic properties, avicins demonstrate cytoprotective effects in non-transformed cells by the activation of Nrf-2 and its downstream targets.[19] These studies indicate that avicins are multi-functional compounds, which may play a role in the maintenance of cellular homeostasis. We demonstrate that avicins can trigger caspase-independent autophagic cell death by the regulation of AMP-activated protein kinase (AMPK)-tuberous sclerosis complex 2 (TSC2)mammalian target of rapamycin (mTOR) pathway, implicating
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