Compartmental stress responses correlate with cell survival in bystander effects induced by the DNA damage agent, bleomycin

Savu, Diana; Petcu, Ileana; Temelie, Mihaela; Mustăciosu, Cosmin Cătălin; Moisoi, Nicoleta

doi:10.1016/j.mrfmmm.2014.11.005

Cited by 10 publications

(5 citation statements)

References 55 publications

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“…The BE has been observed in several species, suggesting it provides a beneficial effect that has been conserved through evolution [72][73][74]. One consequence of BE is an adaptive response that renders bystander cells more resistant to future stressors [52]. Indeed, we have observed that bystander cells that take up EVs released from heat-shocked cells are more resistant to a repeated dose of heat shock [59].…”

Section: (C) Cisplatin Extracellular Vesicles Can Cause Bystander Effect and An Adaptive Response To Cisplatinmentioning

confidence: 59%

“…One consequence of BE is an adaptive response which renders bystander cells more resistant to future stressors (52). Indeed, we have observed that bystander cells that take up EVs released from heat-shocked cells are more resistant to a repeated dose of heat-shock (59).…”

Section: Cisplatin Evs Can Cause Bystander Effect and An Adaptive Resmentioning

confidence: 99%

“…Interestingly, EVs are involved in bystander effect (BE) [48]. BE is a phenomenon in which stressed cells release soluble factors that when taken up by naive recipient cells can induce phenotypic effects, including DNA damage [48][49][50][51][52][53]. The potential roles for EVs released from cisplatin-stressed ovarian cancer cells, particularly in the context of the tumour microenvironment, have not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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Cisplatin induces the release of extracellular vesicles from ovarian cancer cells that can induce invasiveness and drug resistance in bystander cells

Samuel

Mulcahy

Furlong

et al. 2017

Phil. Trans. R. Soc. B

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Ovarian cancer has a poor overall survival that is partly caused by resistance to drugs such as cisplatin. Resistance can be acquired as a result of changes to the tumour or due to altered interactions within the tumour microenvironment. Extracellular vesicles (EVs), small lipid-bound vesicles that are loaded with macromolecular cargo and released by cells, are emerging as mediators of communication in the tumour microenvironment. We previously showed that EVs mediate the bystander effect, a phenomenon in which stressed cells can communicate with neighbouring naive cells leading to various effects including DNA damage; however, the role of EVs released following cisplatin treatment has not been tested. Here we show that treatment of cells with cisplatin led to the release of EVs that could induce invasion and increased resistance when taken up by bystander cells. This coincided with changes in p38 and JNK signalling, suggesting that these pathways may be involved in mediating the effects. We also show that EV uptake inhibitors could prevent this EV-mediated adaptive response and thus sensitize cells in vitro to the effects of cisplatin. Our results suggest that preventing pro-tumourigenic EV cross-talk during chemotherapy is a potential therapeutic target for improving outcome in ovarian cancer patients. This article is part of the discussion meeting issue ‘Extracellular vesicles and the tumour microenvironment’.

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Section: (C) Cisplatin Extracellular Vesicles Can Cause Bystander Effect and An Adaptive Response To Cisplatinmentioning

confidence: 59%

Section: Cisplatin Evs Can Cause Bystander Effect and An Adaptive Resmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cisplatin induces the release of extracellular vesicles from ovarian cancer cells that can induce invasiveness and drug resistance in bystander cells

Samuel

Mulcahy

Furlong

et al. 2017

Phil. Trans. R. Soc. B

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“…Cells were directly exposed to 0–3 Gy of X-ray generated by a medical linear accelerator (Primus Mevatron 2D, 6 MV, Siemens, Germany), at a dose rate of 1.85 Gy/min [ 23 ], or treated with bleomycin sulfate (BLM, Sigma-Aldrich, USA) for 1 hour at 5–40 μ g/mL followed by 3 washes with culture medium [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

“…The endpoints that demonstrate a BE address similar DNA damage and cell survival-cell death as in the case of AR. BE were first considered detrimental secondary effects of radiation exposure, given their manifestation as increased DNA damage, chromosomal aberration, and increased apoptosis in neighboring unexposed cells that may cumulate to induce either cellular death or tumorigenesis [ 22 – 26 ]. However, this view has been challenged by evidence that BE may represent a beneficial, adaptive phenomenon [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Intracellular and Intercellular Signalling Mechanisms following DNA Damage Are Modulated By PINK1

Temelie¹,

Savu²,

Moisoi

2018

Oxidative Medicine and Cellular Longevity

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Impaired mitochondrial function and accumulation of DNA damage have been recognized as hallmarks of age-related diseases. Mitochondrial dysfunction initiates protective signalling mechanisms coordinated at nuclear level particularly by modulating transcription of stress signalling factors. In turn, cellular response to DNA lesions comprises a series of interconnected complex protective pathways, which require the energetic and metabolic support of the mitochondria. These are involved in intracellular as well as in extracellular signalling of damage. Here, we have initiated a study that addresses how mitochondria-nucleus communication may occur in conditions of combined mitochondrial dysfunction and genotoxic stress and what are the consequences of this interaction on the cell system. In this work, we used cells deficient for PINK1, a mitochondrial kinase involved in mitochondrial quality control whose loss of function leads to the accumulation of dysfunctional mitochondria, challenged with inducers of DNA damage, namely, ionizing radiation and the radiomimetic bleomycin. Combined stress at the level of mitochondria and the nucleus impairs both mitochondrial and nuclear functions. Our findings revealed exacerbated sensibility to genotoxic stress in PINK1-deficient cells. The same cells showed an impaired induction of bystander phenomena following stress insults. However, these cells responded adaptively when a challenge dose was applied subsequently to a low-dose treatment to the cells. The data demonstrates that PINK1 modulates intracellular and intercellular signalling pathways, particularly adaptive responses and transmission of bystander signalling, two facets of the cell-protective mechanisms against detrimental agents.

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Bystander effects and compartmental stress response to X-ray irradiation in L929 cells

Temelie

Stroe

Petcu

et al. 2016

Radiat Environ Biophys

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Bystander effects are indirect consequences of radiation and many other stress factors. They occur in cells that are not directly exposed to these factors, but receive signals from affected cells either by gap junctions or by molecules released in the medium. Characterizing these effects and deciphering the underlying mechanisms involved in radiation-induced bystander effects are relevant for cancer radiotherapy and radioprotection. At doses of X-ray radiation 0.5 and 1 Gy, we detected bystander effects as increased numbers of micronuclei shortly after the treatment, through medium transfer and by co-cultures. Interestingly, bystander cells did not exhibit long-term adverse changes in viability. Evaluation of several compartmental stress markers (CHOP, BiP, mtHsp60, cytHsp70) by qRT-PCR did not reveal expression changes at transcriptional level. We investigated the involvement of ROS and NO in this process by addition of specific scavengers of these molecules, DMSO or c-PTIO in the transferred medium. This approach proved that ROS but not NO is involved in the induction of lesions in the acceptor cells. These results indicate that L929 cells are susceptible to stress effects of radiation-induced bystander signaling.

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Compartmental stress responses correlate with cell survival in bystander effects induced by the DNA damage agent, bleomycin

Cited by 10 publications

References 55 publications

Cisplatin induces the release of extracellular vesicles from ovarian cancer cells that can induce invasiveness and drug resistance in bystander cells

Cisplatin induces the release of extracellular vesicles from ovarian cancer cells that can induce invasiveness and drug resistance in bystander cells

Intracellular and Intercellular Signalling Mechanisms following DNA Damage Are Modulated By PINK1

Bystander effects and compartmental stress response to X-ray irradiation in L929 cells

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