F1F0-ATP Synthase Inhibitory Factor 1 in the Normal Pancreas and in Pancreatic Ductal Adenocarcinoma: Effects on Bioenergetics, Invasion and Proliferation

Tanton, Helen; Voronina, Svetlana; Evans, A.G.; Armstrong, J. A.; Sutton, Robert M.; Criddle, David N.; Haynes, Lee P.; Schmid, Michael C.; Campbell, Fiona; Costello, Eithne; Tepikin, Alexei V.

doi:10.3389/fphys.2018.00833

Cited by 6 publications

(8 citation statements)

References 45 publications

(86 reference statements)

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“…A poor prognosis is also accompanied by high IF1 levels in hepatocarcinoma (Song et al, 2014) and stomach cancer (Yin et al, 2015). On the same line, both the downregulation and knockout of IF1 in the PANC-1 pancreatic cancer cells reduced migration, invasion and proliferation, supporting the role of IF1 in growth and metastasis of patients pancreatic ductal adenocarcinoma (Tanton et al, 2018). Importantly, in the latter cellular model it was shown that, in the absence of the inhibitor protein, a drop in mitochondrial membrane potential was observed when cells were subjected to anoxia-mimicking condition (Tanton et al, 2018).…”

Section: If1 and The Metastatic Behavior Of Tumorsmentioning

confidence: 64%

“…This highlights the importance of ATP hydrolysis in cell proliferation, and thus the role of IF1 in the inhibition of this process. Similarly, the pancreatic ductal adenocarcinoma PDAC cell lines, showing a higher IF1 content and IF1/ATP synthase ratio than pancreatic acinar cells PACs, exhibited the ability of maintaining their ATP levels under conditions of chemical hypoxia (Tanton et al, 2018). The rate of ATP hydrolysis was also inhibited by IF1 in intact mitochondria from hepatoma after preincubation with an uncoupler (Chernyak et al, 1991).…”

Section: If1 In Hypoxic Tumors and Atp Hydrolysismentioning

confidence: 95%

“…Although these findings found support by experiments in cultured cells overexpressing or downregulating IF1 (Sánchez-Cenizo et al, 2010), there is intense debate on the latter specific functions of IF1 in the literature (see the recent review by Solaini et al, 2021). The inhibition of ATP synthesis by the inhibitor protein was not matched by the majority of studies reporting measurements of ATP synthesis rate and ΔΨ both in IF1-silenced and control cancer cells (Fujikawa et al, 2012;Runswick et al, 2013;Barbato et al, 2015;Sgarbi et al, 2018a;Tanton et al, 2018). Furthermore, a decrease in ROS formation was described in osteosarcoma cells in which IF1 is stably silenced (Sgarbi et al, 2018b), in line with a slightly decreased state 3 respiration upon IF1 downregulation (Barbato et al, 2015).…”

Section: If1 In Normoxic Tumors and Atp Synthesismentioning

confidence: 96%

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The F1Fo-ATPase inhibitor protein IF1 in pathophysiology

et al. 2022

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The endogenous inhibitor of ATP synthase is a protein of about 10 kDa, known as IF1 which binds to the catalytic domain of the enzyme during ATP hydrolysis. The main role of IF1 consists of limiting ATP dissipation under condition of severe oxygen deprivation or in the presence of dysfunctions of mitochondrial respiratory complexes, causing a collapse in mitochondrial membrane potential and therefore ATP hydrolysis. New roles of IF1 are emerging in the fields of cancer and neurodegeneration. Its high expression levels in tumor tissues have been associated with different roles favouring tumor formation, progression and evasion. Since discordant mechanisms of action have been proposed for IF1 in tumors, it is of the utmost importance to clarify them in the prospective of defining novel approaches for cancer therapy. Other IF1 functions, including its involvement in mitophagy, may be protective for neurodegenerative and aging-related diseases. In the present review we aim to clarify and discuss the emerging mechanisms in which IF1 is involved, providing a critical view of the discordant findings in the literature.

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Section: If1 and The Metastatic Behavior Of Tumorsmentioning

confidence: 64%

Section: If1 In Hypoxic Tumors and Atp Hydrolysismentioning

confidence: 95%

Section: If1 In Normoxic Tumors and Atp Synthesismentioning

confidence: 96%

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The F1Fo-ATPase inhibitor protein IF1 in pathophysiology

et al. 2022

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“…It is not clear how ATP5B gene expression and ecto-ATP5B levels are related in any given cell type; ATP5B protein is subject to substantial post-translational and functional regulation, including plasma membrane redistribution [ 16 , 38 – 41 ]. However, several components of the ATP synthase complex have been reported to be upregulated in cancer [ 40 , 42 , 43 ]. We therefore asked whether ATP5B expression was associated with cancer phenotypes in clinical populations by comparing ATP5B transcript levels in tumor vs. normal tissue in multiple prostate and breast cancer datasets.…”

Section: Resultsmentioning

confidence: 99%

A novel RNA aptamer identifies plasma membrane ATP synthase beta subunit as an early marker and therapeutic target in aggressive cancer

Speransky

Serafini

Caroli

et al. 2019

Breast Cancer Res Treat

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Purpose Primary breast and prostate cancers can be cured, but metastatic disease cannot. Identifying cell factors that predict metastatic potential could guide both prognosis and treatment. Methods We used Cell-SELEX to screen an RNA aptamer library for differential binding to prostate cancer cell lines with high vs. low metastatic potential. Mass spectroscopy, immunoblot, and immunohistochemistry were used to identify and validate aptamer targets. Aptamer properties were tested in vitro, in xenograft models, and in clinical biopsies. Gene expression datasets were queried for target associations in cancer. Results We identified a novel aptamer (Apt63) that binds to the beta subunit of F 1 F o ATP synthase (ATP5B), present on the plasma membrane of certain normal and cancer cells. Apt63 bound to plasma membranes of multiple aggressive breast and prostate cell lines, but not to normal breast and prostate epithelial cells, and weakly or not at all to non-metastasizing cancer cells; binding led to rapid cell death. A single intravenous injection of Apt63 induced rapid, tumor cell-selective binding and cytotoxicity in MDA-MB-231 xenograft tumors, associated with endonuclease G nuclear translocation and DNA fragmentation. Apt63 was not toxic to non-transformed epithelial cells in vitro or adjacent normal tissue in vivo. In breast cancer tissue arrays, plasma membrane staining with Apt63 correlated with tumor stage ( p < 0.0001, n = 416) and was independent of other cancer markers. Across multiple datasets, ATP5B expression was significantly increased relative to normal tissue, and negatively correlated with metastasis-free ( p = 0.0063, 0.00039, respectively) and overall ( p = 0.050, 0.0198) survival. Conclusion Ecto-ATP5B binding by Apt63 may disrupt an essential survival mechanism in a subset of tumors with high metastatic potential, and defines a novel category of cancers with potential vulnerability to ATP5B-targeted therapy. Apt63 is a unique tool for elucidating the function of surface ATP synthase, and potentially for predicting and treating metastatic breast and prostate cancer. Electronic supplementary material The online version of this article (10.1007/s10549-019-05174-3) contains supplementary material, which is available to authorized users.

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“…IF1 is upregulated in many tumors and cancer cells, which may promote cancer cell survival [ 12 , 13 , 14 , 15 ]. Eliminating IF1 in various cancer cell lines modified cellular bioenergetics and decreased migration, invasion, and proliferation [ 16 , 17 ]. However, how cellular changes of IF1 impact cellular energetics, cell viability, and proliferation remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

IF1 Promotes Cellular Proliferation and Inhibits Oxidative Phosphorylation in Mouse Embryonic Fibroblasts under Normoxia and Hypoxia

Lauterboeck,

Kang,

White

et al. 2024

Cells

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ATP synthase inhibitory factor subunit 1 (IF1) is an inhibitory subunit of mitochondrial ATP synthase, playing a crucial role in regulating mitochondrial respiration and energetics. It is well-established that IF1 interacts with the F1 sector of ATP synthase to inhibit the reversal rotation and, thus, ATP hydrolysis. Recent evidence supports that IF1 also inhibits forward rotation or the ATP synthesis activity. Adding to the complexity, IF1 may also facilitate mitophagy and cristae formation. The implications of these complex actions of IF1 for cellular function remain obscure. In the present study, we found that IF1 expression was markedly upregulated in hypoxic MEFs relative to normoxic MEFs. We investigate how IF1 affects cellular growth and function in cultured mouse embryonic fibroblasts derived from mouse lines with systemic IF1 overexpression and knockout under normoxia and hypoxia. Cell survival and proliferation analyses revealed that IF1 overexpression exerted limited effects on cellular viability but substantially increased proliferation under normoxia, whereas it facilitated both cellular viability and proliferation under hypoxia. The absence of IF1 may have a pro-survival effect but not a proliferative one in both normoxia and hypoxia. Cellular bioenergetic analyses revealed that IF1 suppressed cellular respiration when subjected to normoxia and was even more pronounced when subjected to hypoxia with increased mitochondrial ATP production. In contrast, IF1 knockout MEFs showed markedly increased cellular respiration under both normoxia and hypoxia with little change in mitochondrial ATP. Glycolytic stress assay revealed that IF1 overexpression modestly increased glycolysis in normoxia and hypoxia. Interestingly, the absence of IF1 in MEFs led to substantial increases in glycolysis. Therefore, we conclude that IF1 mainly inhibits cellular respiration and enhances cellular glycolysis to preserve mitochondrial ATP. On the other hand, IF1 deletion can significantly facilitate cellular respiration and glycolysis without leading to mitochondrial ATP deficit.

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F1F0-ATP Synthase Inhibitory Factor 1 in the Normal Pancreas and in Pancreatic Ductal Adenocarcinoma: Effects on Bioenergetics, Invasion and Proliferation

Cited by 6 publications

References 45 publications

The F1Fo-ATPase inhibitor protein IF1 in pathophysiology

The F1Fo-ATPase inhibitor protein IF1 in pathophysiology

A novel RNA aptamer identifies plasma membrane ATP synthase beta subunit as an early marker and therapeutic target in aggressive cancer

IF1 Promotes Cellular Proliferation and Inhibits Oxidative Phosphorylation in Mouse Embryonic Fibroblasts under Normoxia and Hypoxia

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