Extracellular ATP, as an energy and phosphorylating molecule, induces different types of drug resistances in cancer cells through ATP internalization and intracellular ATP level increase

Wang, Xuan; Li, Yunsheng; Qian, Yanrong; Cao, Yanyang; Shriwas, Pratik; Zhang, Haiyun; Chen, Xiaozhuo

doi:10.18632/oncotarget.21231

Cited by 61 publications

(83 citation statements)

References 47 publications

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“…The synthesis of ATP occurs via the oxidative phosphorylation of glucose or via the canonical mitochondrial oxidation pathway from ATP synthetase, and thus cellular metabolism is maintained in a tight energy homeostasis through regulation of ATP levels . Cancer cells have been shown to have higher ATP levels than normal cells in vitro, and decreasing ATP means the cancer cells are entering conditions of apoptosis or necrosis . As shown in Figure C, treating MAD‐MA‐231 cells with IR‐783 significantly decreased the intracellular level of ATP.…”

Section: Resultsmentioning

confidence: 95%

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

Tang

Liu

Zhang

et al. 2018

J Cellular Molecular Medi

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IR‐783 is a kind of heptamethine cyanine dye that exhibits imaging, cancer targeting and anticancer properties. A previous study reported that its imaging and targeting properties were related to mitochondria. However, the molecular mechanism behind the anticancer activity of IR‐783 has not been well demonstrated. In this study, we showed that IR‐783 inhibits cell viability and induces mitochondrial apoptosis in human breast cancer cells. Exposure of MDA‐MB‐231 cells to IR‐783 resulted in the loss of mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) depletion, mitochondrial permeability transition pore (mPTP) opening and cytochrome c (Cyto C) release. Furthermore, we found that IR‐783 induced dynamin‐related protein 1 (Drp1) translocation from the cytosol to the mitochondria, increased the expression of mitochondrial fission proteins mitochondrial fission factor (MFF) and fission‐1 (Fis1), and decreased the expression of mitochondrial fusion proteins mitofusin1 (Mfn1) and optic atrophy 1 (OPA1). Moreover, knockdown of Drp1 markedly blocked IR‐783‐mediated mitochondrial fission, loss of MMP, ATP depletion, mPTP opening and apoptosis. Our in vivo study confirmed that IR‐783 markedly inhibited tumour growth and induced apoptosis in an MDA‐MB‐231 xenograft model in association with the mitochondrial translocation of Drp1. Taken together, these findings suggest that IR‐783 induces apoptosis in human breast cancer cells by increasing Drp1‐mediated mitochondrial fission. Our study uncovered the molecular mechanism of the anti‐breast cancer effects of IR‐783 and provided novel perspectives for the application of IR‐783 in the treatment of breast cancer.

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Section: Resultsmentioning

confidence: 95%

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

Tang

Liu

Zhang

et al. 2018

J Cellular Molecular Medi

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“…(C) General scheme for ascorbate (ASC) and glutathione (GSH) cycle in (Continued) processes (78). Additionally, it can be internalized by tumor cells, increasing their intracellular ATP levels conferring metabolic reprogramming, increased tumor aggressivity, and treatment resistance (79)(80)(81)(82)(83). A recent lung cancer study has shown eATP to be involved in epithelial-to-mesenchymal transition, cell migration, and metastasis (84).…”

Section: Discussionmentioning

confidence: 99%

Radiation Induced Metabolic Alterations Associate With Tumor Aggressiveness and Poor Outcome in Glioblastoma

et al. 2020

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Glioblastoma (GBM) is uniformly fatal with a 1-year median survival, despite best available treatment, including radiotherapy (RT). Impacts of prior RT on tumor recurrence are poorly understood but may increase tumor aggressiveness. Metabolic changes have been investigated in radiation-induced brain injury; however, the tumor-promoting effect following prior radiation is lacking. Since RT is vital to GBM management, we quantified tumor-promoting effects of prior RT on patient-derived intracranial GBM xenografts and characterized metabolic alterations associated with the protumorigenic microenvironment. Human xenografts (GBM143) were implanted into nude mice 24 hrs following 20 Gy cranial radiation vs. sham animals. Tumors in pre-radiated mice were more proliferative and more infiltrative, yielding faster mortality (p < 0.0001). Histologic evaluation of tumor associated macrophage/microglia (TAMs) revealed cells with a more fully activated ameboid morphology in pre-radiated animals. Microdialyzates from radiated brain at the margin of tumor infiltration contralateral to the site of implantation were analyzed by unsupervised liquid chromatography-mass spectrometry (LC-MS). In pre-radiated animals, metabolites known to be associated with tumor progression (i.e., modified nucleotides and polyols) were identified. Whole-tissue metabolomic analysis of pre-radiated brain microenvironment for metabolic alterations in a separate cohort of nude mice using 1 H-NMR revealed a significant decrease in levels of antioxidants (glutathione (GSH) and ascorbate (ASC)), NAD + , Tricarboxylic acid cycle (TCA) intermediates, and rise in energy carriers (ATP, GTP). GSH and ASC showed highest Variable Importance on Projection prediction (VIPpred) (1.65) in Orthogonal Partial least square Discriminant Analysis (OPLS-DA); Ascorbate catabolism was identified by GC-MS. To assess longevity of radiation effects, we compared survival with implantation occurring 2 months vs. 24 hrs following radiation, finding worse survival in animals implanted at 2 months. These radiation-induced alterations are consistent with a chronic disease-like microenvironment characterized by reduced levels of antioxidants and NAD + , and elevated extracellular ATP and GTP serving as chemoattractants, promoting cell motility and vesicular secretion with decreased levels of GSH and ASC exacerbating oxidative stress. Gupta et al. RT-Induced Microenvironmental Metabolic Alterations in Glioblastoma Taken together, these data suggest IR induces tumor-permissive changes in the microenvironment with metabolomic alterations that may facilitate tumor aggressiveness with important implications for recurrent glioblastoma. Harnessing these metabolomic insights may provide opportunities to attenuate RT-associated aggressiveness of recurrent GBM.

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“…Extracellular ATP is known to induce resistance to various chemotherapeutic drugs in cancer cells. Interestingly, drug resistance to sunitinib in NSCLC tumour cells is linked to macropinocytic uptake because it is suppressed by knockdown of PAK1, a known regulator of macropinocytosis [60]. The uptake of ATP via macropinocytosis is a prime example that macropinocytic cargo can vary in tumour cells, and depending on the context, identifying novel cargoes could provide clues to the breadth of function for macropinocytosis in cancer [46,61].…”

Section: Lung Cancermentioning

confidence: 99%

The pervasiveness of macropinocytosis in oncological malignancies

Commisso

2018

Phil. Trans. R. Soc. B

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In tumour cells, macropinocytosis functions as an amino acid supply route and supports cancer cell survival and proliferation. Initially demonstrated in oncogenic KRAS -driven models of pancreatic cancer, macropinocytosis triggers the internalization of extracellular proteins via discrete endocytic vesicles called macropinosomes. The incoming protein cargo is targeted for lysosome-dependent degradation, causing the intracellular release of amino acids. These protein-derived amino acids support metabolic fitness by contributing to the intracellular amino acid pools, as well as to the biosynthesis of central carbon metabolites. In this way, macropinocytosis represents a novel amino acid supply route that tumour cells use to survive the nutrient-poor conditions of the tumour microenvironment. Macropinocytosis has also emerged as an entry mechanism for a variety of nanomedicines, suggesting that macropinocytosis regulation in the tumour setting can be harnessed for the delivery of anti-cancer therapeutics. A slew of recent studies point to the possibility that macropinocytosis is a pervasive feature of many different tumour types. In this review, we focus on the role of this important uptake mechanism in a variety of cancers and highlight the main molecular drivers of macropinocytosis in these malignancies. This article is part of the Theo Murphy meeting issue ‘Macropinocytosis’.

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Extracellular ATP, as an energy and phosphorylating molecule, induces different types of drug resistances in cancer cells through ATP internalization and intracellular ATP level increase

Cited by 61 publications

References 47 publications

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

Dynamin‐related protein 1‐mediated mitochondrial fission contributes to IR‐783‐induced apoptosis in human breast cancer cells

Radiation Induced Metabolic Alterations Associate With Tumor Aggressiveness and Poor Outcome in Glioblastoma

The pervasiveness of macropinocytosis in oncological malignancies

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