Differential redox sensitivity of cathepsin B and L holds the key to autophagy-apoptosis interplay after Thioredoxin reductase inhibition in nutritionally stressed SH-SY5Y cells

Nagakannan, Pandian; Eftekharpour, Eftekhar

doi:10.1016/j.freeradbiomed.2017.05.005

Cited by 29 publications

(25 citation statements)

References 48 publications

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“…The phosphoinositol 3 kinase/Akt/mTOR signaling pathway and the Ras/Raf1/ERK1/2 pathway are known to regulate autophagy in cellular responses ( 31 , 32 ). In the present study, the activation of mTOR signaling was demonstrated and the conversion of LC3-I to LC3-II was decreased by AA1 treatment, which is consistent with observations of other types of cancer treated with TrxR inhibitors ( 33 , 34 ). Targeting TrxR induces the inhibition of autophagy independently of ROS.…”

Section: Discussionsupporting

confidence: 92%

Inhibiting TrxR suppresses liver cancer by inducing apoptosis and eliciting potent antitumor immunity

et al. 2018

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Liver cancer is one of the most common malignant tumors worldwide. Thioredoxin reductase (TrxR) is highly expressed in liver cancer cells. The present study aimed to investigate the effect of inhibiting TrxR on liver cancer and to better understand the underlying molecular and immunological mechanisms associated with inhibition. It was demonstrated that targeting TrxR inhibited the growth and induced apoptosis of liver cancer cells, which was accompanied by activation of the mitogen associated protein kinase pathway. This inhibition was dependent on the production of reactive oxygen species (ROS). Blockage of ROS production reversed TrxR inhibitor-induced antitumor effects. Blocking the Trx/TrxR system activated the mammalian target of rapamycin pathway and inhibited autophagy, which occurred in a ROS-independent manner. TrxR inhibition led to lesions in the mitochondrial membrane, indicated by alterations in membrane potential. Mouse xenograft experiments were highly consistent with in vitro studies. Most importantly, blocking the Trx/TrxR system improved the tumor immune microenvironment. Together, these data demonstrated that TrxR is a potential target for liver cancer therapy, which could inhibit hepatocarcinogenesis and progression, and improve the antitumor immune response.

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Section: Discussionsupporting

confidence: 92%

Inhibiting TrxR suppresses liver cancer by inducing apoptosis and eliciting potent antitumor immunity

et al. 2018

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“…However, there was no significant difference in the content of LAMP-2 protein between 27-OHC and control treatments in C6 cells. These results indicated that in both cell lines 27-OHC treatment leads to enlargement of lysosomes (Nagakannan and Eftekharpour, 2017), which has been suggested to increase the possibility of lysosomes losing their integrity, leading to leakage of lysosomal content to the cytosol (Appelqvist et al, 2013).…”

Section: Resultsmentioning

confidence: 89%

“…To observe the effect of 27-OHC on the function of lysosome, we examined the changes in protein content and enzymatic activity of CTSB and CTSD in SH-SY5Y cells and C6 cells. The active form of CTSB (24 and 27 kDa) was detected by western blot (Nagakannan and Eftekharpour, 2017). We found that 27-OHC treatment significantly regulated the protein content of CTSB and CTSD in both SH-SY5Y cells and C6 cells.…”

Section: Resultsmentioning

confidence: 99%

27-Hydroxycholesterol Contributes to Lysosomal Membrane Permeabilization-Mediated Pyroptosis in Co-cultured SH-SY5Y Cells and C6 Cells

Chen

Zhou

et al. 2019

Front. Mol. Neurosci.

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Purpose : Emerging evidence suggests that 27-Hydroxycholesterol (27-OHC) causes neurodegenerative diseases through the induction of cytotoxicity and cholesterol metabolism disorder. The objective of this study is to determine the impacts of 27-OHC on lysosomal membrane permeabilization (LMP) and pyroptosis in neurons in the development of neural degenerative diseases. Methods : In this study, SH-SY5Y cells and C6 cells were co-cultured in vitro to investigate the influence of 27-OHC on the function of lysosome, LMP and pyroptosis related factors in neuron. Lyso Tracker Red (LTR) was used to detect the changes of lysosome pH, volume and number. Acridine orange (AO) staining was also used to detect the LMP in neurons. Then the morphological changes of cells were observed by a scanning electron microscope (SEM). The content of lysosome function associated proteins [including Cathepsin B (CTSB), Cathepsin D (CTSD), lysosomal-associated membraneprotein-1 (LAMP-1), LAMP-2] and the pyroptosis associated proteins [including nod-like recepto P3 (NLRP3), gasdermin D (GSDMD), caspase-1 and interleukin (IL)-1β] were detected through Western blot. Results : Results showed higher levels of lysosome function associated proteins, such as CTSB ( p < 0.05), CTSD ( p < 0.05), LAMP-1 ( p < 0.01), LAMP-2; p < 0.01) in 27-OHC treated group than that in the control group. AO staining and LTR staining showed that 27-OHC induced lysosome dysfunction with LMP. Content of pyroptosis related factor proteins, such as GSDMD ( p < 0.01), NLRP3 ( p < 0.001), caspase-1 ( p < 0.01) and IL-1β ( p < 0.01) were increased in 27-OHC treated neurons. Additionally, CTSB was leaked through LMP into the cytosol and induced pyroptosis. Results from the present study also suggested that the CTSB is involved in activation of pyroptosis. Conclusion : Our data indicate that 27-OHC contributes to the pathogenesis of cell death by inducing LMP and pyroptosis in neurons.

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“…Our lab has recently shown that the level of ROS can affect cell-signaling machinery between cell survival and cell death [ 33 ]; therefore, the levels of ROS must be tightly regulated. We further showed that oxidative modification of methionine residues in cathepsin L may be responsible for a balance between the protective autophagy and apoptosis [ 34 ]. The thiol group in glutathione, thioredoxin, and glutaredoxins has a low redox potential enabling them to act as an electron buffering pool and therefore a central player in the regulation of cell signaling.…”

Section: Role Of Ros In Cell Signaling: a Basic Understandingmentioning

confidence: 99%

Regulatory Role of Redox Balance in Determination of Neural Precursor Cell Fate

Iqbal

Eftekharpour

2017

Stem Cells International

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In 1990s, reports of discovery of a small group of cells capable of proliferation and contribution to formation of new neurons in the central nervous system (CNS) reversed a century-old concept on lack of neurogenesis in the adult mammalian brain. These cells are found in all stages of human life and contribute to normal cellular turnover of the CNS. Therefore, the identity of regulating factors that affect their proliferation and differentiation is a highly noteworthy issue for basic scientists and their clinician counterparts for therapeutic purposes. The cues for such control are embedded in developmental and environmental signaling through a highly regulated tempo-spatial expression of specific transcription factors. Novel findings indicate the importance of reactive oxygen species (ROS) in the regulation of this signaling system. The elusive nature of ROS signaling in many vital processes from cell proliferation to cell death creates a complex literature in this field. Here, we discuss the emerging thoughts on the importance of redox regulation of proliferation and maintenance in mammalian neural stem and progenitor cells under physiological and pathological conditions. The current knowledge on ROS-mediated changes in redox-sensitive proteins that govern the molecular mechanisms in proliferation and differentiation of these cells is reviewed.

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Differential redox sensitivity of cathepsin B and L holds the key to autophagy-apoptosis interplay after Thioredoxin reductase inhibition in nutritionally stressed SH-SY5Y cells

Cited by 29 publications

References 48 publications

Inhibiting TrxR suppresses liver cancer by inducing apoptosis and eliciting potent antitumor immunity

Inhibiting TrxR suppresses liver cancer by inducing apoptosis and eliciting potent antitumor immunity

27-Hydroxycholesterol Contributes to Lysosomal Membrane Permeabilization-Mediated Pyroptosis in Co-cultured SH-SY5Y Cells and C6 Cells

Regulatory Role of Redox Balance in Determination of Neural Precursor Cell Fate

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