SCO2 Induces p53-Mediated Apoptosis by Thr<sup>845</sup> Phosphorylation of ASK-1 and Dissociation of the ASK-1–Trx Complex

Madan, Esha; Gogna, Rajan; Kuppusamy, Periannan; Bhatt, Madan Lal Brahma; Mahdi, Abbas Ali; Pati, Uttam

doi:10.1128/mcb.06798-11

Cited by 37 publications

(26 citation statements)

References 47 publications

(92 reference statements)

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“…The unaffected levels of SCO2 in LACE1 overexpressing cells further confirm the extranuclear, transcription-independent character of LACE1-induced p53 upregulation. Besides its function in complex IV assembly, the SCO2 metallochaperone was identified as a p53 transcription target gene required for shift of cellular metabolism from glycolysis to increased OXPHOS utilization [26–28]. On the other hand, positive genetic interaction between the mitochondrial metallopeptidase OMA1 and p53 was observed in OVCA cells, which is consistent with LACE1-induced OMA1 upregulation seen in our HEK293 knockdown model [29].…”

Section: Discussionsupporting

confidence: 76%

LACE1 interacts with p53 and mediates its mitochondrial translocation and apoptosis

et al. 2016

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p53 is a major cellular tumor suppressor that in addition to its nuclear, transcription-dependent activity is also known to function extranuclearly. Cellular stressors such as reactive oxygen species can promote translocation of p53 into mitochondria where it acts to protect mitochondrial genome or trigger cell death via transcription-independent manner. Here we report that the mammalian homologue of yeast mitochondrial Afg1 ATPase (LACE1) promotes translocation of p53 into mitochondria. We further show that LACE1 exhibits significant pro-apoptotic activity, which is dependent on p53, and that the protein is required for normal mitochondrial respiratory function. LACE1 physically interacts with p53 and is necessary for mitomycin c-induced translocation of p53 into mitochondria. Conversely, increased expression of LACE1 partitions p53 to mitochondria, causes reduction in nuclear p53 content and induces apoptosis. Thus, LACE1 mediates mitochondrial translocation of p53 and its transcription-independent apoptosis.

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Section: Discussionsupporting

confidence: 76%

LACE1 interacts with p53 and mediates its mitochondrial translocation and apoptosis

et al. 2016

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“…For this reason, the role of ASK1 in the biological activity of the four bioactive compounds was evaluated. The phosphorylation of ASK1 at Ser-967 has been related to differentiation in other cell types [36] whereas phosphorylation of ASK1 at Thr-845 has been associated with apoptosis induction [37]. The level of endogenous ASK1 and phosphorylated forms, P-ASK1 Thr845 or P-ASK1 Ser 967 were studied in prostate cancer cells.…”

Section: Resultsmentioning

confidence: 99%

Thioredoxin 1 modulates apoptosis induced by bioactive compounds in prostate cancer cells

et al. 2017

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Accumulating evidence suggests that natural bioactive compounds, alone or in combination with traditional chemotherapeutic agents, could be used as potential therapies to fight cancer. In this study, we employed four natural bioactive compounds (curcumin, resveratrol, melatonin, and silibinin) and studied their role in redox control and ability to promote apoptosis in androgen sensitive and insensitive prostate cancer cells. Here is shown that curcumin and resveratrol promote ROS production and induce apoptosis in LNCaP and PC-3. An increase in reactive species is a trigger event in curcumin-induced apoptosis and a consequence of resveratrol effects on other pathways within these cells. Moreover, here we demonstrated that these four compounds affect differently one of the main intracellular redox regulator, the thioredoxin system. Exposure to curcumin and resveratrol promoted TRX1 oxidation and altered its subcellular location. Furthermore, resveratrol diminished TRX1 levels in PC-3 cells and increased the expression of its inhibitor TXNIP. Conversly, melatonin and silibinin only worked as cytostatic agents, reducing ROS levels and showing preventive effects against TRX oxidation. All together, this work explores the effect of compounds currently tested as chemo-preventive agents in prostate cancer therapy, on the TRX1 redox state and function. Our work shows the importance that the TRX system might have within the differences found in their mechanisms of action. These bioactive compounds trigger different responses and affect ROS production and redox systems in prostate cancer cells, suggesting the key role that redox-related pathways might play in processes like differentiation or survival in prostate cancer.

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“…Treatment with H 2 O 2 or chemotherapy can increase TIGAR expression while antioxidants have the opposite effect . Glioblastoma was found to highly express TIGAR, which was necessary for survival while restricting both glucose and oxygen . Likewise, the mitochondrial biogenesis factor PGC‐1 increases antioxidant enzyme expression to reduce ROS and compensate for higher oxidative phosphorylation.…”

Section: Antioxidant Enzymes and Glutaminolysis Can Facilitate Advancmentioning

confidence: 99%

Reactive oxygen species (ROS) are a key determinant of cancer's metabolic phenotype

Rodic

Vincent

2017

Intl Journal of Cancer

152

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Cancer cells exhibit a wide range of metabolic phenotypes, ranging from strict aerobic glycolysis to increased mitochondrial respiration. The cause and utility of this metabolic variation is poorly understood. Given that cancer cells experience heavy selection within their microenvironment, survival requires metabolic adaptation to both extracellular and intracellular conditions. Herein, we suggest that reactive oxygen species (ROS) are a key determinant of cancer's metabolic phenotype. Intracellular ROS levels can be modified by an assortment of critical parameters including oxygenation, glucose availability and growth factors. ROS act as integrators of environmental information as well as downstream effectors of signaling pathways. Maintaining ROS within a narrow range allows malignant cells to enhance growth and invasion while limiting their apoptotic susceptibility. Cancer cells actively modify their metabolism to optimize intracellular ROS levels and thereby improve survival. Furthermore, we highlight distinct metabolic phenotypes in response to oxidative stress and their tumorigenic drivers.

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SCO2 Induces p53-Mediated Apoptosis by Thr⁸⁴⁵ Phosphorylation of ASK-1 and Dissociation of the ASK-1–Trx Complex

Cited by 37 publications

References 47 publications

LACE1 interacts with p53 and mediates its mitochondrial translocation and apoptosis

LACE1 interacts with p53 and mediates its mitochondrial translocation and apoptosis

Thioredoxin 1 modulates apoptosis induced by bioactive compounds in prostate cancer cells

Reactive oxygen species (ROS) are a key determinant of cancer's metabolic phenotype

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SCO2 Induces p53-Mediated Apoptosis by Thr845 Phosphorylation of ASK-1 and Dissociation of the ASK-1–Trx Complex

Cited by 37 publications

References 47 publications

LACE1 interacts with p53 and mediates its mitochondrial translocation and apoptosis

LACE1 interacts with p53 and mediates its mitochondrial translocation and apoptosis

Thioredoxin 1 modulates apoptosis induced by bioactive compounds in prostate cancer cells

Reactive oxygen species (ROS) are a key determinant of cancer's metabolic phenotype

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Product

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SCO2 Induces p53-Mediated Apoptosis by Thr⁸⁴⁵ Phosphorylation of ASK-1 and Dissociation of the ASK-1–Trx Complex