Safety control for apoptotic irreversibility

Dutreix, Marie

doi:10.1073/pnas.1210736109

Cited by 3 publications

(3 citation statements)

References 16 publications

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“…Thus, our results could be explained by the role of p-HSP90α in DDR or apoptosis given that Thr5/7 phosphorylation has not been previously implicated in the regulation of its chaperone activities 40,41. It has been hypothesized that phosphorylation of HSP90α by DNA-PK could play a role in disabling its cytoprotective functions to trigger apoptosis, preventing that the cells with damage chromosomes can escape this process 42…”

Section: Discussionmentioning

confidence: 76%

“…40,41 It has been hypothesized that phosphorylation of HSP90α by DNA-PK could play a role in disabling its cytoprotective functions to trigger apoptosis, preventing that the cells with damage chromosomes can escape this process. 42 The functional alterations of DDR mediators are associated with tumor development and chemotherapy resistance. 5,11 Because of its role as DNA damage signaling factor, γH2AX has been proposed as a biomarker for early cancer detection, prognosis, and sensitivity to cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

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DNA Damage Repair Proteins, HSP27, and Phosphorylated-HSP90α as Predictive/Prognostic Biomarkers of Platinum-based Cancer Chemotherapy: An Exploratory Study

Sottile

Cuello-Carrión²,

Gómez

et al. 2022

Applied Immunohistochemistry &Amp; Molecular Morphology

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Platinum analogs are commonly used for cancer treatment. There is increasing interest in finding biomarkers which could predict and overcome resistance, because to date there is no reliable predictive/prognostic marker for these compounds. Here we studied the immunohistochemical expression of proteins involved in DNA damage response and repair (γH2AX, 53BP1, ERCC1, MLH1, and MSH2) in primary tumor tissues from patients treated with platinum-based chemotherapy. Levels and localization of Heat Shock Protein (HSP)27 and phospho-(Thr5/7)-HSP90α (p-HSP90α) were also determined. The implications in clinical response, disease-free survival and overall survival were analyzed. High γH2AX and 53BP1 expressions were associated with poor clinical response. Nuclear p-HSP90α, as well as nuclear absence and low cytoplasmic expression of HSP27 correlated with good response. Patients with high γH2AX and high cytoplasmic HSP27 expressions had shorter overall survival and disease-free survival. MLH1, MSH2, or ERCC1 were not associated with clinical response or survival. We report the potential utility of p-HSP90α, HSP27, γH2AX, and 53BP1 as predictive/prognostic markers for platinum-based chemotherapy. We present the first study that evaluates the predictive and prognostic value of p-HSP90α in primary tumors. Our research opens new possibilities for clinical oncology and shows the usefulness of immunohistochemistry for predicting chemotherapy response and prognosis in cancer.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

DNA Damage Repair Proteins, HSP27, and Phosphorylated-HSP90α as Predictive/Prognostic Biomarkers of Platinum-based Cancer Chemotherapy: An Exploratory Study

Sottile

Cuello-Carrión²,

Gómez

et al. 2022

Applied Immunohistochemistry &Amp; Molecular Morphology

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“…While the mitochondria-located intrinsic pathway can be activated by the wide range of cellular stress signals (such as DNA damage, ER stress), the extrinsic pathway is initiated by death-receptors [55,57]. Apoptosis should always be an irreversible process; once the cell has decided to commit suicide, it can never return [53,58]. That is why apoptosis must not be triggered by weak signals, and the cell must not hesitate on the borderline of non-apoptotic and apoptotic state; otherwise, it can have serious consequences for the cellular system [59].…”

Section: Er Stress Can Induce Both Autophagy and Apoptosismentioning

confidence: 99%

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

Kapuy

2024

IJMS

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Dynamic regulation of the cellular proteome is mainly controlled in the endoplasmic reticulum (ER). Accumulation of misfolded proteins due to ER stress leads to the activation of unfolded protein response (UPR). The primary role of UPR is to reduce the bulk of damages and try to drive back the system to the former or a new homeostatic state by autophagy, while an excessive level of stress results in apoptosis. It has already been proven that the proper order and characteristic features of both surviving and self-killing mechanisms are controlled by negative and positive feedback loops, respectively. The new results suggest that these feedback loops are found not only within but also between branches of the UPR, fine-tuning the response to ER stress. In this review, we summarize the recent knowledge of the dynamical characteristic of endoplasmic reticulum stress response mechanism by using both theoretical and molecular biological techniques. In addition, this review pays special attention to describing the mechanism of action of the dynamical features of the feedback loops controlling cellular life-and-death decision upon ER stress. Since ER stress appears in diseases that are common worldwide, a more detailed understanding of the behaviour of the stress response is of medical importance.

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Basal State Calibration of a Chemical Reaction Network Model for Autophagy

Hajdú,

Kapuy,

Nagy

2024

IJMS

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The modulation of autophagy plays a dual role in tumor cells, with the potential to both promote and suppress tumor proliferation. In order to gain a deeper understanding of the nature of autophagy, we have developed a chemical reaction kinetic model of autophagy and apoptosis based on the mass action kinetic models that have been previously described in the literature. It is regrettable that the authors did not provide all of the information necessary to reconstruct their model, which made their simulation results irreproducible. In this study, based on an extensive literature review, we have identified concentrations for each species in the stress-free, homeostatic state. These ranges were randomly sampled to generate sets of initial concentrations, from which the simulations were run. In every case, abnormal behavior was observed, with apoptosis and autophagy being activated, even in the absence of stress. Consequently, the model failed to reproduce even the basal conditions. Detailed examination of the model revealed erroneous reactions, which were corrected. The influential kinetic parameters of the corrected model were identified and optimized using the Optima++ code. The model is now capable of simulating homeostatic states, and provides a suitable basis for further model development to describe cell response to various stresses.

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Safety control for apoptotic irreversibility

Cited by 3 publications

References 16 publications

DNA Damage Repair Proteins, HSP27, and Phosphorylated-HSP90α as Predictive/Prognostic Biomarkers of Platinum-based Cancer Chemotherapy: An Exploratory Study

DNA Damage Repair Proteins, HSP27, and Phosphorylated-HSP90α as Predictive/Prognostic Biomarkers of Platinum-based Cancer Chemotherapy: An Exploratory Study

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

Basal State Calibration of a Chemical Reaction Network Model for Autophagy

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