Ectopic expression of the ATP synthase β subunit on the membrane of PC-3M cells supports its potential role in prostate cancer metastasis

Li, Wei; Li, Yulin; Li, Gaiyun; Zhou, Zilong; Chang, Xiaona; Xia, Yang; Dong, Xinjie; Liu, Zhijing; Ren, Bo; Liu, Wei; Li, Yilei

doi:10.3892/ijo.2017.3878

Cited by 25 publications

(22 citation statements)

References 34 publications

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“…Activation of A 3 R suppressed prostate cancer metastasis ( Jajoo et al, 2009 ). The ATP synthase β subunit also plays a role in prostate cancer metastasis ( Li W. et al, 2017 ).…”

Section: Diseases Of the Reproductive Systemmentioning

confidence: 99%

Purinergic Signalling: Therapeutic Developments

2017

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Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.

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“…Activation of A 3 R suppressed prostate cancer metastasis ( Jajoo et al, 2009 ). The ATP synthase β subunit also plays a role in prostate cancer metastasis ( Li W. et al, 2017 ).…”

Section: Diseases Of the Reproductive Systemmentioning

confidence: 99%

Purinergic Signalling: Therapeutic Developments

2017

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“…Considerable evidence links ecto-ATP synthase to aggressive cancer cell growth. Plasma membrane-associated ATP5 subunits, including ATP5B, have been correlated with more-aggressive, larger and more advanced tumors, in multiple cancers including breast, lung, and prostate [ 17 , 42 , 64 ]. In our breast cancer TMA analysis of Apt63 binding, including biopsies representing 416 subjects, surface ATP5B appears to define a unique subset of highly aggressive breast and prostate cancers, present on 45% of DCIS and 55% of invasive ductal carcinomas, and on almost all (91.3%) lymph node metastases.…”

Section: Discussionmentioning

confidence: 99%

“…The biological importance of ecto-ATPase has been explored using a range of physiological and synthetic ligands, including angiostatin, plasminogen, monoclonal antibodies, peptides, and small molecules binding to the F 1 module [ 12 , 14 , 16 , 64 – 67 ]. The effects of these agents are both cell type and ligand-specific, but most reduce extracellular ATP production and cell proliferation, and some initiate programmed death.…”

Section: Discussionmentioning

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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“…The ATP synthase complex is composed of the membrane-embedded F0 component and soluble catalytic F1 component, and our results that cancer cells survive regular BAMLET dosing by downregulating ATP synthase is consistent with the hypothesis of ATP synthase as a membrane target of BAMLET. Proton-pumping, energy-generating F0F1 ATP synthase has been identified as present on the plasma membrane of cancer cells [ 93 – 96 ] whereas in most types of healthy cells it is located in the mitochondria and not on the plasma membrane, which suggests that ATP synthase could be an effective potential target for anti-cancer therapy. The membrane-embedded c-ring of F0 ATP synthase has been demonstrated to be capable of forming a pore when in high calcium conditions [ 97 ].…”

Section: Discussionmentioning

confidence: 99%

BAMLET kills chemotherapy-resistant mesothelioma cells, holding oleic acid in an activated cytotoxic state

et al. 2018

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Malignant pleural mesothelioma is an aggressive cancer with poor prognosis. Here we have investigated in vitro efficacy of BAMLET and BLAGLET complexes (anti-cancer complexes consisting of oleic acid and bovine α-lactalbumin or β-lactoglobulin respectively) in killing mesothelioma cells, determined BAMLET and BLAGLET structures, and investigated possible biological mechanisms. We performed cell viability assays on 16 mesothelioma cell lines. BAMLET and BLAGLET having increasing oleic acid content inhibited human and rat mesothelioma cell line proliferation at decreasing doses. Most of the non-cancer primary human fibroblasts were more resistant to BAMLET than were human mesothelioma cells. BAMLET showed similar cytotoxicity to cisplatin-resistant, pemetrexed-resistant, vinorelbine-resistant, and parental rat mesothelioma cells, indicating the BAMLET anti-cancer mechanism may be different to drugs currently used to treat mesothelioma. Cisplatin, pemetrexed, gemcitabine, vinorelbine, and BAMLET, did not demonstrate a therapeutic window for mesothelioma compared with immortalised non-cancer mesothelial cells. We demonstrated by quantitative PCR that ATP synthase is downregulated in mesothelioma cells in response to regular dosing with BAMLET. We sought structural insight for BAMLET and BLAGLET activity by performing small angle X-ray scattering, circular dichroism, and scanning electron microscopy. Our results indicate the structural mechanism by which BAMLET and BLAGLET achieve increased cytotoxicity by holding increasing amounts of oleic acid in an active cytotoxic state encapsulated in increasingly unfolded protein. Our structural studies revealed similarity in the molecular structure of the protein components of these two complexes and in their encapsulation of the fatty acid, and differences in the microscopic structure and structural stability. BAMLET forms rounded aggregates and BLAGLET forms long fibre-like aggregates whose aggregation is more stable than that of BAMLET due to intermolecular disulphide bonds. The results reported here indicate that BAMLET and BLAGLET may be effective second-line treatment options for mesothelioma.

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Ectopic expression of the ATP synthase β subunit on the membrane of PC-3M cells supports its potential role in prostate cancer metastasis

Cited by 25 publications

References 34 publications

Purinergic Signalling: Therapeutic Developments

Purinergic Signalling: Therapeutic Developments

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

BAMLET kills chemotherapy-resistant mesothelioma cells, holding oleic acid in an activated cytotoxic state

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