Carbonyl cyanide <i>p</i>‐trifluoromethoxyphenylhydrazone (FCCP) induces initiation factor 2α phosphorylation and translation inhibition in PC12 cells

Muñoz, F.; Martín, María Eugenia; Salinas, Matilde; Fando, Juan L.

doi:10.1016/s0014-5793(01)02247-5

Cited by 6 publications

(3 citation statements)

References 22 publications

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“…Thus, inhibition of protein synthesis caused by mitochondrial poisons correlates with phosphorylation of eEF2 (an event known to impair overall protein synthesis) but is not accompanied by any change in the phosphorylation of another regulator of total protein synthesis, eIF2. This differs from the conclusions of Munoz et al [28], who, using a quite different cell type (PC12 cells), found that CCCP treatment did cause an increase in the phosphorylation of eIF2α. This effect was not observed in our study, indicating that this is not a universal response of mammalian cells to ATP depletion.…”

Section: Resultscontrasting

confidence: 99%

ATP depletion increases phosphorylation of elongation factor eEF2 in adult cardiomyocytes independently of inhibition of mTOR signalling

McLeod

Proud

2002

FEBS Letters

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Translation elongation consumes a high proportion of cellular energy and can be regulated by phosphorylation of elongation factor eEF2 which inhibits its activity. We have studied the e¡ects of ATP depletion on the phosphorylation of eEF2 in adult rat ventricular cardiomyocytes. Energy depletion rapidly leads to inhibition of protein synthesis and increased phosphorylation of eEF2. Stimulation of the AMP-activated protein kinase also causes increases eEF2 phosphorylation. Only at later times is an e¡ect on mTOR signalling observed. These data suggest that energy depletion leads to inhibition of protein synthesis through phosphorylation of eEF2 independently of inhibition of mTOR signalling.

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Section: Resultscontrasting

confidence: 99%

ATP depletion increases phosphorylation of elongation factor eEF2 in adult cardiomyocytes independently of inhibition of mTOR signalling

McLeod

Proud

2002

FEBS Letters

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“…To test whether mitochondrial inhibition could induce dormancy in C4-2B cells, we examined the effects of well-established mitochondrial inhibitors. We found that rotenone or IACS-010759 (IACS), both the respiration complex I inhibitors [ 60 , 61 ], and FCCP, a potent uncoupler of oxidative phosphorylation in mitochondria [ 62 ], inhibited C4-2B proliferation in a dose-dependent manner (Supplementary Figure S6 A). However, despite inhibiting C4-2B proliferation, various doses of rotenone and IACS significantly decreased the expression of dormancy marker NR2F1 at 24 to 72 h (Supplementary Figure S6 B).…”

Section: Resultsmentioning

confidence: 99%

Tumor removal limits prostate cancer cell dissemination in bone and osteoblasts induce cancer cell dormancy through focal adhesion kinase

Liu,

Su,

Xing

et al. 2023

J Exp Clin Cancer Res

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Background Disseminated tumor cells (DTCs) can enter a dormant state and cause no symptoms in cancer patients. On the other hand, the dormant DTCs can reactivate and cause metastases progression and lethal relapses. In prostate cancer (PCa), relapse can happen after curative treatments such as primary tumor removal. The impact of surgical removal on PCa dissemination and dormancy remains elusive. Furthermore, as dormant DTCs are asymptomatic, dormancy-induction can be an operational cure for preventing metastases and relapse of PCa patients. Methods We used a PCa subcutaneous xenograft model and species-specific PCR to survey the DTCs in various organs at different time points of tumor growth and in response to tumor removal. We developed in vitro 2D and 3D co-culture models to recapitulate the dormant DTCs in the bone microenvironment. Proliferation assays, fluorescent cell cycle reporter, qRT-PCR, and Western Blot were used to characterize the dormancy phenotype. We performed RNA sequencing to determine the dormancy signature of PCa. A drug repurposing algorithm was applied to predict dormancy-inducing drugs and a top candidate was validated for the efficacy and the mechanism of dormancy induction. Results We found DTCs in almost all mouse organs examined, including bones, at week 2 post-tumor cell injections. Surgical removal of the primary tumor reduced the overall DTC abundance, but the DTCs were enriched only in the bones. We found that osteoblasts, but not other cells of the bones, induced PCa cell dormancy. RNA-Seq revealed the suppression of mitochondrial-related biological processes in osteoblast-induced dormant PCa cells. Importantly, the mitochondrial-related biological processes were found up-regulated in both circulating tumor cells and bone metastases from PCa patients’ data. We predicted and validated the dormancy-mimicking effect of PF-562,271 (PF-271), an inhibitor of focal adhesion kinase (FAK) in vitro. Decreased FAK phosphorylation and increased nuclear translocation were found in both co-cultured and PF-271-treated C4-2B cells, suggesting that FAK plays a key role in osteoblast-induced PCa dormancy. Conclusions Our study provides the first insights into how primary tumor removal enriches PCa cell dissemination in the bones, defines a unique osteoblast-induced PCa dormancy signature, and identifies FAK as a PCa cell dormancy gatekeeper.

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“…To test whether mitochondrial inhibition could induce dormancy in C4-2B cells, we examined the effects of well-established mitochondrial inhibitors. We found that rotenone or IACS-010759 (IACS), both the respiration complex I inhibitors [60, 61], and FCCP, a potent uncoupler of oxidative phosphorylation in mitochondria [62], inhibited C4-2B proliferation in a dose-dependent manner ( Supplementary Figure S6A ). However, despite inhibiting C4-2B proliferation, various doses of rotenone and IACS significantly decreased the expression of dormancy marker NR2F1 at 24 to 72 hours ( Supplementary Figure S6B) .…”

Section: Resultsmentioning

confidence: 99%

Tumor removal limits prostate cancer cell dissemination in bone and osteoblasts induce cancer cell dormancy through focal adhesion kinase

Liu

Su²,

Liu

et al. 2022

Preprint

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Primary prostate cancer (PCa) cells can disseminate early and stay dormant in distant organs but reactivate later, causing lethal metastasis and recurrence. The mechanisms of PCa cell dissemination, dormancy, and reactivation are overlooked, especially whether and how various treatments affect these processes. Using C4-2B PCa subcutaneous xenograft mouse model, we found that in mice with xenograft tumor removed, the disseminated tumor cells (DTC) were exclusively enriched in the bones, more specifically, in the bone cortex instead of the bone marrow. We hypothesize that DTC are dormant in the bone cortex and proliferative in the bone marrow and developed an in vitro mixed co-culture model to determine the bone stromal cell type inducing the dormancy. We found that osteoblasts, but not other stromal cells induced C4-2B PCa cell into a dormancy-like state, i.e., slowed proliferation without increased apoptosis, G0/G1 arrest, increased expression of dormancy marker, and decreased expression of proliferation markers. Through RNA-sequencing, gene ontology, and public dataset analyses, we found a reverse correlation between mitochondrial gene expressions and enrichment of mitochondria-related functions and PCa progression. We further predicted dormancy-mimicking drugs using a novel artificial intelligence (AI) platform. One of the candidates, PF-562271, a focal adhesion kinase (FAK) inhibitor, was validated as dormancy-mimicking in vitro. Altogether, our study revealed for the first time the effects of primary tumor removal on PCa cell dissemination, profiled the osteoblasts-induced C4-2B cell dormancy, and induced PCa cell dormancy in vitro using AI predicted drugs, which could potentially inhibit PCa bone metastasis progression and recurrence clinically.

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Carbonyl cyanide p‐trifluoromethoxyphenylhydrazone (FCCP) induces initiation factor 2α phosphorylation and translation inhibition in PC12 cells

Cited by 6 publications

References 22 publications

ATP depletion increases phosphorylation of elongation factor eEF2 in adult cardiomyocytes independently of inhibition of mTOR signalling

ATP depletion increases phosphorylation of elongation factor eEF2 in adult cardiomyocytes independently of inhibition of mTOR signalling

Tumor removal limits prostate cancer cell dissemination in bone and osteoblasts induce cancer cell dormancy through focal adhesion kinase

Tumor removal limits prostate cancer cell dissemination in bone and osteoblasts induce cancer cell dormancy through focal adhesion kinase

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