“…[49][50][51] Recent studies have indicated that PARP1 activation is required for DNA damage and oxidative injury-mediated autophagy in normal or cancer cells. 32,52,53 In the present study, we show that HMGB1 function is downstream of PARP1 activation to mediate TNFSF10-induced autophagy. The activity of PARP1 is not significantly impaired in TNFSF10-resistant cells compared to TNFSF10-sensitive cells.…”
Abbreviations: ATG, autophagy-related; DISC, death-inducing signaling complex; HMGB1, high mobility group box 1; MAP1LC3A/LC3, microtubule-associated protein 1 light chain 3 a; PARP1, poly (ADP-ribose) polymerase 1; PARylation, poly-ADP-ribosylation; RIPK1/RIP, receptor (TNFRSF)-interacting serine-threonine kinase 1; shRNA, short hairpin RNA; TNFSF10/TRAIL, tumor necrosis factor (ligand) superfamily, member 10; TNF, tumor necrosis factor; TUNEL, TdT-mediated dUTP-X nick end labelingBoth apoptosis ("self-killing") and autophagy ("self-eating") are evolutionarily conserved processes, and their crosstalk influences anticancer drug sensitivity and cell death. However, the underlying mechanism remains unclear. Here, we demonstrated that HMGB1 (high mobility group box 1), normally a nuclear protein, is a crucial regulator of TNFSF10/TRAIL (tumor necrosis factor [ligand] superfamily, member 10)-induced cancer cell death. Activation of PARP1 (poly [ADP-ribose] polymerase 1) was required for TNFSF10-induced ADP-ribosylation of HMGB1 in cancer cells. Moreover, pharmacological inhibition of PARP1 activity or knockdown of PARP1 gene expression significantly inhibited TNFSF10-induced HMGB1 cytoplasmic translocation and subsequent HMGB1-BECN1 complex formation. Furthermore, suppression of the PARP1-HMGB1 pathway diminished autophagy, increased apoptosis, and enhanced the anticancer activity of TNFSF10 in vitro and in a subcutaneous tumor model. These results indicate that PARP1 acts as a prominent upstream regulator of HMGB1-mediated autophagy and maintains a homeostatic balance between apoptosis and autophagy, which provides new insight into the mechanism of TNFSF10 resistance.
“…[49][50][51] Recent studies have indicated that PARP1 activation is required for DNA damage and oxidative injury-mediated autophagy in normal or cancer cells. 32,52,53 In the present study, we show that HMGB1 function is downstream of PARP1 activation to mediate TNFSF10-induced autophagy. The activity of PARP1 is not significantly impaired in TNFSF10-resistant cells compared to TNFSF10-sensitive cells.…”
Abbreviations: ATG, autophagy-related; DISC, death-inducing signaling complex; HMGB1, high mobility group box 1; MAP1LC3A/LC3, microtubule-associated protein 1 light chain 3 a; PARP1, poly (ADP-ribose) polymerase 1; PARylation, poly-ADP-ribosylation; RIPK1/RIP, receptor (TNFRSF)-interacting serine-threonine kinase 1; shRNA, short hairpin RNA; TNFSF10/TRAIL, tumor necrosis factor (ligand) superfamily, member 10; TNF, tumor necrosis factor; TUNEL, TdT-mediated dUTP-X nick end labelingBoth apoptosis ("self-killing") and autophagy ("self-eating") are evolutionarily conserved processes, and their crosstalk influences anticancer drug sensitivity and cell death. However, the underlying mechanism remains unclear. Here, we demonstrated that HMGB1 (high mobility group box 1), normally a nuclear protein, is a crucial regulator of TNFSF10/TRAIL (tumor necrosis factor [ligand] superfamily, member 10)-induced cancer cell death. Activation of PARP1 (poly [ADP-ribose] polymerase 1) was required for TNFSF10-induced ADP-ribosylation of HMGB1 in cancer cells. Moreover, pharmacological inhibition of PARP1 activity or knockdown of PARP1 gene expression significantly inhibited TNFSF10-induced HMGB1 cytoplasmic translocation and subsequent HMGB1-BECN1 complex formation. Furthermore, suppression of the PARP1-HMGB1 pathway diminished autophagy, increased apoptosis, and enhanced the anticancer activity of TNFSF10 in vitro and in a subcutaneous tumor model. These results indicate that PARP1 acts as a prominent upstream regulator of HMGB1-mediated autophagy and maintains a homeostatic balance between apoptosis and autophagy, which provides new insight into the mechanism of TNFSF10 resistance.
“…At both 8 and 12 h time points, we observed that rasonin induced the cleavage of PARP-1 (Figure 1B), suggesting that rasfonin activates apoptotic pathway. Using flow cytometry, we found that rasfonin-induced cell death could be either apoptotic or necrotic (Figure 1C) (Zhang et al 2011; Klionsky 2012). 10.1080/21501203.2016.1147091-F0001Figure 1.Rasfonin induces multiple cell death pathways.…”
Two major protein quality control mechanisms exist in eukaryotic cells, the ubiquitin-proteasome system (UPS) and the autophagy–lysosome system. Generally, the inhibition of UPS is believed to enhance autophagic pathway; nevertheless, the crosstalk between these two degradation systems may be much more complicated. Rasfonin, a 2-pyrone derivative of fungal secondary metabolites, is demonstrated to have the antitumor effect and can function as an autophagy inducer. Here, we reported that rasfonin activated multiple cell death pathways, including caspase-dependent apoptosis. Using electroscopy and microscopy, we observed rasfonin increased the formation of autophagosome. In immunoblotting assay, rasfonin enhanced autophagic flux concomitant with the upregulation of ubiquitination. MG132, an inhibitor of proteasome, attenuated rasfonin-dependent autophagy, whereas its presentation stimulated rasfonin-induced cleavage of poly (ADP-ribose) polymerase, a marker of caspase-dependent apoptosis. Together, we demonstrated that rasfonin induced the activation of both UPS and autophagic pathway, and the inhibition of UPS attenuated rasfonin-induced autophagy and enhanced the cytotoxicity of rasonin by upregulation of caspase-dependent apoptosis.
“…In our former study (Zhang et al 2011), we reported that 11ʹ-deoxyverticillin A (C42), a member of a class of fungal secondary metabolites known as epipolythiodioxopiperazines (ETPs), could induce autophagy and necrotic cell death of tumour cells through RIP1. Similarly, in this study, we found that the inhibition of necroptosis increased caspase-dependent apoptosis by rasfonin, and affected the induced autophagy depending on stimulation duration.…”
Rasfonin (A304) is a fungal natural product isolated from the fermentation substrate of Talaromyces sp. 3656-A1, which was named according to its activity against the small G-protein Ras. In a former study, we demonstrated that it induced autophagy and apoptosis; however, whether rasfonin activated necroptosis remained unknown. Moreover, the interplay among different cell death processes induced by rasfonin was unexplored. In the present study, we revealed that, in addition of promoting autophagy and caspase-dependent apoptosis, rasfonin also activated necroptosis. Nectrostatin-1 (Nec-1), an inhibitor of necroptosis, affected rasfonin-induced autophagy in a time-dependent manner concurring with an increased caspase-dependent apoptosis. The aforementioned results were confirmed by knockdown of receptor-interacting protein 1 (RIP1), a crucial necrostatin-1-targeted adaptor kinase mediating cell death and survival. Taken together, the data presented indicate that rasfonin activates various cell death pathways, and RIP1 plays a critical role in rasfonin-induced autophagy and apoptosis.
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