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    • Accumulating data suggest that ROS trigger autophagy but

    2024-01-29

    Accumulating data suggest that ROS trigger autophagy but, in turn, autophagy reduces ROS levels [23]. Our results are in agreement because 27-OH mediated autophagy induction interms of LC3 II formation and Beclin 1 protein expression was suppressed by treating the promonocytic cells with the antioxidant NAC (Fig. 4C). Consistently, 7-K was shown to be involved in pro-survival autophagic response, specifically Beclin 1 transcription that regulated by a mitochondrial enzyme, proline oxidase-dependent ROS in oxLDL challenged cancer cells [55]. Another critical observation was that cell supplementation with either NAC or DPI prevents the induction of p62 expression by 27-OH (Fig. 4A,B). Several recent reports establish a role for p62 in delivering oxidized proteins to autophagosomes for the removal of these protein (-)-Bicuculline methiodide sale [23]. Moreover, Mathew et al. indicated p62 as a new critical player in cancer showing that impairment in autophagy leads to p62 accumulation, thereby promoting tumorigenesis [56]. Notably, a feed-forward loop between ROS and p62 contributes to this process; in particular, excessive ROS induces p62 expression while, in turn, enforced p62 expression induces ROS production as part of an amplifying loop, thereby promoting genome instability. Besides the demonstration that induction of autophagic response in 27-OH treated cells was ROS-dependent, of note autophagy modulation by chemical inhibitor and inducers in turn was able to regulate ROS levels. As mentioned in the Introduction, the redox-sensitive transcription factor Nrf2 and autophagy are both involved in oxidative stress response to antagonize cellular stressing signals by promoting a series of antioxidant programs. In fact, as shown in Fig. 5, both p62 and Nrf2 synthesis as we expected were abrogated by mTOR inhibitor Torin 1. It can be suggested that, in response to oxidative stress, autophagy and Nrf2 would be in negative interaction with each other, in particular if Nrf2 antioxidant pathways is suppressed, the further activation of autophagy is required to reduce ROS accumulation to ensure adaptive cell survival. Consistently, suppression of autophagy at particular stages with different inhibitors enhanced Nrf2 expression and nuclear translocation upon ROS stimulation in pancreatic cancer cells [57]. Certainly all results obtained by using inhibitors should be taken with caution. Hence, all our data concerning the modulation of Nrf2 via autophagy are fully consistent among them and further indirectly validated by using both Nrf2 siRNA and antibody (Fig. 6). To summarize, our data support the hypothesis that in 27-OH treated cells induction of autophagy by low concentrations of the oxysterol is required for the cell survival, as well as for the induction of cytoprotective responses, i.e. stimulation of Nrf2 antioxidant response (graphical abstract). Notably, autophagy induced by 27-OH is, in part, mediated by oxidative stress and that an increase in intracellular ROS is quenched by activated survival signals including redox-sensitive Nrf2. Both mitochondrial depolarization and Nox-2 activity contribute to the pro-oxidant effect of the oxysterol. Moreover, 27-OH-induced MEK/ERK and PI3K/Akt pathways play regulatory role in oxysterol-mediated pro-survival autophagy. In the current study, we speculated that ROS plays a key role in autophagy and in the activation of Nrf2 pathway. In this connection, 27-OH leads to p62 accumulation thus activating Nrf2 pathway, while the oxysterol pro-oxidant effect activates Nrf2 pathway against the intracellular ROS generation. It can be suggested that autophagy and Nrf2 activation might function as a adaptive survival response and resistance mechanism against the previously established pro-apoptotic action of 27-OH [19] to delay macrophage apoptosis that favor growth and destabilization of advanced atherosclerotic plaques [58]. Further studies are needed to assess the interplay between autophagy and apoptosis in our proposed model. Since both Nrf2 and autophagy contribute to the chemoresistance, and the interplay between cell death pathways and autophagy has important pathophysiological consequences, developing therapeutic interventions to target these crosstalks are exciting prospects for future studies.