The Dual Role of Sulforaphane-Induced Cellular Stress—A Systems Biological Study

Abstract

The endoplasmic reticulum (ER) plays a crucial role in cellular homeostasis. When ER stress is generated, an autophagic self-digestive process is activated to promote cell survival; however, cell death is induced in the case of excessive levels of ER stress. The aim of the present study was to investigate the effect of a natural compound called sulforaphane (SFN) upon ER stress. Our goal was to investigate how SFN-dependent autophagy activation affects different stages of ER stress induction. We approached our scientific analysis from a systems biological perspective using both theoretical and molecular biological techniques. We found that SFN induced the various cell-death mechanisms in a concentration- and time-dependent manner. The short SFN treatment at low concentrations promoted autophagy, whereas the longer treatment at higher concentrations activated cell death. We proved that SFN activated autophagy in a mTORC1-dependent manner and that the presence of ULK1 was required for its function. A low concentration of SFN pre- or co-treatment combined with short and long ER stress was able to promote cell survival via autophagy induction in each treatment, suggesting the potential medical importance of SFN in ER stress-related diseases.

Mechanism of Decision Making between Autophagy and Apoptosis Induction upon Endoplasmic Reticulum Stress

“…Where the curves intersect, the systems might come to rest at a steady state, which can be stable or unstable (see black or white dots on Figure 2b) [59,105]. The phase plane of the autophagy and apoptosis inducers is plotted under physiological conditions (panel left), at low (middle panel) and high (panel right) level of ER stress, respectively [59,107,108].…”

“…With the drastic increase of ER stress, the balance curve of the autophagy inducer does not move, but the balance curve of the apoptosis inducer shifts to the right resulting in the loss of the autophagic steady state (Figure 2b, panel right) [59,107,108]. In this case, the autophagic valley disappears, and the ball representing the system "rolls over" into the only stable state, which corresponds to apoptotic cell death [107], namely, the regulatory system goes to the sole remaining stable state, which corresponds to apoptosis [107].…”

“…While inhibition of autophagy increases cell death [120,121], rapamycin (an mTOR inhibitor) treatment induced autophagy-promoted cell survival [107,122]. In Kapuy's lab, various natural agents (such as resveratrol, EGCG, sulforaphane) have been successfully used in recent years to delay apoptotic cell death by autophagy induction with respect to excessive levels of ER stress [76,108,123]. Holczer et al have also demonstrated by computer simulation that pretreatment with various enhancers of autophagy greatly delays apoptotic cell death, even in the presence of intolerable ER stress (Figure 2c, panel right) [76,108,123].…”

Voacangine protects hippocampal neuronal cells against oxygen–glucose deprivation/reoxygenation‐caused oxidative stress and ferroptosis by activating the PI3K‐Akt‐FoxO signaling

“…We speculated that because of differences in the absorption capacity of different cell lines for the compound, voacangine exhibited a dual effect of promoting and inhibiting the PI3K-Akt-FoxO signaling pathway, even though we administered similar concentrations. This speculation is not unreasonable, as compounds exhibiting dual effects because of concentration differences have been widely reported (Holczer, Besze, Lehel, & Kapuy, 2024;Sun et al, 2022). Furthermore, the OGD/R model may also contribute to phenotypic heterogeneity, as the absence of glucose leads to alterations in cellular physiological functions, thereby affecting the responsiveness of neuronal cells to voacangine in various ways (Li, Zheng, Zhang, Zhou, & Fan, 2023;Xian et al, 2021).…”