Cross Talk Between Cellular Redox State and the Antiapoptotic Protein Bcl-2

Pöhl, Sebastian; Agostino, Mark; Dharmarajan, Arun; Pervaiz, Shazib

doi:10.1089/ars.2017.7414

Cited by 29 publications

(21 citation statements)

References 193 publications

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“…These changes certainly affect mitochondrial ROS homeostasis due to different rates of ROS production and/or removal; since ROS are the prevailing oxidants in cells, they are crucial players in determining the redox state of the cells. The latter has to be strictly controlled because it can affect cells [ 33 ]. Therefore, to properly design therapeutic interventions against cancer cells, it is of paramount importance to define both cellular level and parameters affecting ROS, considering in particular the oxygen concentrations experienced by that type of cell.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia and IF1 Expression Promote ROS Decrease in Cancer Cells

Sgarbi

Gorini

Liuzzi

et al. 2018

Cells

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The role of reactive oxygen species (ROS) in the metabolic reprogramming of cells adapted to hypoxia and the interplay between ROS and hypoxia in malignancy is under debate. Here, we examined how ROS levels are modulated by hypoxia in human cancer compared to untransformed cells. Short time exposure (20 min) of either fibroblasts or 143B osteosarcoma cells to low oxygen tension down to 0.5% induced a significant decrease of the cellular ROS level, as detected by the CellROX fluorescent probe (−70%). Prolonging the cells’ exposure to hypoxia for 24 h, ROS decreased further, reaching nearly 20% of the normoxic value. In this regard, due to the debated role of the endogenous inhibitor protein (IF1) of the ATP synthase complex in cancer cell bioenergetics, we investigated whether IF1 is involved in the control of ROS generation under severe hypoxic conditions. A significant ROS content decrease was observed in hypoxia in both IF1-expressing and IF1- silenced cells compared to normoxia. However, IF1-silenced cells showed higher ROS levels compared to IF1-containing cells. In addition, the MitoSOX Red-measured superoxide level of all the hypoxic cells was significantly lower compared to normoxia; however, the decrease was milder than the marked drop of ROS content. Accordingly, the difference between IF1-expressing and IF1-silenced cells was smaller but significant in both normoxia and hypoxia. In conclusion, the interplay between ROS and hypoxia and its modulation by IF1 have to be taken into account to develop therapeutic strategies against cancer.

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Section: Discussionmentioning

confidence: 99%

Hypoxia and IF1 Expression Promote ROS Decrease in Cancer Cells

Sgarbi

Gorini

Liuzzi

et al. 2018

Cells

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“…263 For example, Bcl-2 can "sense" the magnitude of ROS production in response to post-translational modifications, namely Ser70 phosphorylation, 264 and changes in Bcl-2 can then impact ETC function, mitochondrial antioxidant capacity, and autophagic flux. 263 The robustness of the Bcl-2 response to ROS levels can determine whether a cell undergoes apoptosis. Our work demonstrates that enhancing mitochondrial JNK signaling by increasing Sab levels amplifies ROS production and renders cells sensitive to chemical insults in part by diminishing OMM Bcl-2 levels.…”

Section: Con Clud Ing Remark S and Future Direc Tionsmentioning

confidence: 99%

Phosphoregulation on mitochondria: Integration of cell and organelle responses

2019

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Mitochondria are highly integrated organelles that are crucial to cell adaptation and mitigating adverse physiology. Recent studies demonstrate that fundamental signal transduction pathways incorporate mitochondrial substrates into their biological programs. Reversible phosphorylation is emerging as a useful mechanism to modulate mitochondrial function in accordance with cellular changes. Critical serine/threonine protein kinases, such as the c‐Jun N‐terminal kinase (JNK), protein kinase A (PKA), PTEN‐induced kinase‐1 (PINK1), and AMP‐dependent protein kinase (AMPK), readily translocate to the outer mitochondrial membrane (OMM), the interface of mitochondria‐cell communication. OMM protein kinases phosphorylate diverse mitochondrial substrates that have discrete effects on organelle dynamics, protein import, respiratory complex activity, antioxidant capacity, and apoptosis. OMM phosphorylation events can be tempered through the actions of local protein phosphatases, such as mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) and protein phosphatase 2A (PP2A), to regulate the extent and duration of signaling. The central mediators of OMM signal transduction are the scaffold proteins because the relative abundance of these accessory proteins determines the magnitude and duration of a signaling event on the mitochondrial surface, which dictates the biological outcome of a local signal transduction pathway. The concentrations of scaffold proteins, such as A‐kinase anchoring proteins (AKAPs) and Sab (or SH3 binding protein 5—SH3BP5), have been shown to influence neuronal survival and vulnerability, respectively, in models of Parkinson's disease (PD), highlighting the importance of OMM signaling to health and disease. Despite recent progress, much remains to be discovered concerning the mechanisms of OMM signaling. Nonetheless, enhancing beneficial OMM signaling events and inhibiting detrimental protein‐protein interactions on the mitochondrial surface may represent highly selective approaches to restore mitochondrial health and homeostasis and mitigate organelle dysfunction in conditions such as PD.

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“…It blocks programmed cell death and augments cell survival under different situations in various cell types [ 31 , 32 ]. The expression of Bcl-2 is intensely connected with the expression of several antioxidant enzymes and the strong relationship controlling the intracellular redox concentration has an essential action in cell destiny [ 33 ].…”

Section: Radiotherapy and Oxidative Stressmentioning

confidence: 99%

Radioprotective Agents and Enhancers Factors. Preventive and Therapeutic Strategies for Oxidative Induced Radiotherapy Damages in Hematological Malignancies

et al. 2020

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Radiation therapy plays a critical role in the management of a wide range of hematologic malignancies. It is well known that the post-irradiation damages both in the bone marrow and in other organs are the main causes of post-irradiation morbidity and mortality. Tumor control without producing extensive damage to the surrounding normal cells, through the use of radioprotectors, is of special clinical relevance in radiotherapy. An increasing amount of data is helping to clarify the role of oxidative stress in toxicity and therapy response. Radioprotective agents are substances that moderate the oxidative effects of radiation on healthy normal tissues while preserving the sensitivity to radiation damage in tumor cells. As well as the substances capable of carrying out a protective action against the oxidative damage caused by radiotherapy, other substances have been identified as possible enhancers of the radiotherapy and cytotoxic activity via an oxidative effect. The purpose of this review was to examine the data in the literature on the possible use of old and new substances to increase the efficacy of radiation treatment in hematological diseases and to reduce the harmful effects of the treatment.

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Cross Talk Between Cellular Redox State and the Antiapoptotic Protein Bcl-2

Cited by 29 publications

References 193 publications

Hypoxia and IF1 Expression Promote ROS Decrease in Cancer Cells

Hypoxia and IF1 Expression Promote ROS Decrease in Cancer Cells

Phosphoregulation on mitochondria: Integration of cell and organelle responses

Radioprotective Agents and Enhancers Factors. Preventive and Therapeutic Strategies for Oxidative Induced Radiotherapy Damages in Hematological Malignancies

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