Depending on their tissue of origin, genetic and epigenetic marks and microenvironmental influences, cancer cells cover a broad range of metabolic activities that fluctuate over time and space. At ...the core of most metabolic pathways, mitochondria are essential organelles that participate in energy and biomass production, act as metabolic sensors, control cancer cell death, and initiate signaling pathways related to cancer cell migration, invasion, metastasis and resistance to treatments. While some mitochondrial modifications provide aggressive advantages to cancer cells, others are detrimental. This comprehensive review summarizes the current knowledge about mitochondrial transfers that can occur between cancer and nonmalignant cells. Among different mechanisms comprising gap junctions and cell-cell fusion, tunneling nanotubes are increasingly recognized as a main intercellular platform for unidirectional and bidirectional mitochondrial exchanges. Understanding their structure and functionality is an important task expected to generate new anticancer approaches aimed at interfering with gains of functions (e.g., cancer cell proliferation, migration, invasion, metastasis and chemoresistance) or damaged mitochondria elimination associated with mitochondrial transfer.
Mitochondria in cancer Grasso, Debora; Zampieri, Luca X.; Capelôa, Tânia ...
Cell Stress,
06/2020, Letnik:
4, Številka:
6
Journal Article
Recenzirano
Odprti dostop
The rediscovery and reinterpretation of the Warburg effect in the year 2000 occulted for almost a decade the key functions exerted by mitochondria in cancer cells. Until recent times, the scientific ...community indeed focused on constitutive glycolysis as a hallmark of cancer cells, which it is not, largely ignoring the contribution of mitochondria to the malignancy of oxidative and glycolytic cancer cells, being Warburgian or merely adapted to hypoxia. In this review, we highlight that mitochondria are not only powerhouses in some cancer cells, but also dynamic regulators of life, death, proliferation, motion and stemness in other types of cancer cells. Similar to the cells that host them, mitochondria are capable to adapt to tumoral conditions, and probably to evolve to ‘oncogenic mitochondria' capable of transferring malignant capacities to recipient cells. In the wider quest of metabolic modulators of cancer, treatments have already been identified targeting mitochondria in cancer cells, but the field is still in infancy.
Ovarian cancer is an aggressive disease that affects about 300,000 patients worldwide, with a yearly death count of about 185,000. Following surgery, treatment involves adjuvant or neoadjuvant ...administration of taxane with platinum compounds cisplatin or carboplatin, which alkylate DNA through the same chemical intermediates. However, although platinum-based therapy can cure patients in a number of cases, a majority of them discontinues treatment owing to side effects and to the emergence of resistance. In this study, we focused on resistance to cisplatin and investigated whether metabolic changes could be involved. As models, we used matched pairs of cisplatin-sensitive (SKOV-3 and COV-362) and cisplatin-resistant (SKOV-3-R and COV-362-R) human ovarian carcinoma cells that were selected in vitro following exposure to increasing doses of the chemotherapy. Metabolic comparison revealed that resistant cells undergo a shift towards a more oxidative metabolism. The shift goes along with a reorganization of the mitochondrial network, with a generally increased mitochondrial compartment. More functional mitochondria in cisplatin-resistant compared to cisplatin-sensitive cells were associated to enzymatic changes affecting either the electron transport chain (SKOV-3/SKOV-3-R model) or mitochondrial coupling (COV-362/COV-362-R model). Our findings further indicate that the preservation of functional mitochondria in these cells could be due to an increased mitochondrial turnover rate, suggesting mitophagy inhibition as a potential strategy to tackle cisplatin-resistant human ovarian cancer progression. Implications: Besides classical mechanisms related to drug efflux and target modification, we report that preserving functional mitochondria is a strategy used by human ovarian cancer cells to resist to cisplatin chemotherapy.
We present a systematic analysis of the X-ray spectra of NGC 1313 X-1 and NGC 1313 X-2, using three years of XMM-Newton observations. We fitted the continuum with a Comptonization model plus a ...multicolour blackbody disc, which describes the effects of an accretion disc plus a corona. We checked the consistency of this spectral model on the basis of the variability patterns of its spectral parameters. We found that the two sources show different spectral states. We tentatively interpret the observed behaviour of NGC 1313 X-1 and X-2 within the framework of near-Eddington and/or super-Eddington accretion. We also attempted to determine the chemical abundances in the local environment of NGC 1313 X-1 and X-2 from the EPIC and RGS spectra. The results appear to indicate subsolar metallicity for both sources.
Anthracyclines Doxorubicin, Epirubicin, Daunorubicin and Idarubicin are used to treat a variety of tumor types in the clinics, either alone or, most often, in combination therapies. While their ...cardiotoxicity is well known, the emergence of chemoresistance is also a major issue accounting for treatment discontinuation. Resistance to anthracyclines is associated to the acquisition of multidrug resistance conferred by overexpression of permeability glycoprotein-1 or other efflux pumps, by altered DNA repair, changes in topoisomerase II activity, cancer stemness and metabolic adaptations. This review further details the metabolic aspects of resistance to anthracyclines, emphasizing the contributions of glycolysis, the pentose phosphate pathway and nucleotide biosynthesis, glutathione, lipid metabolism and autophagy to the chemoresistant phenotype.
In cancer, mitochondrial functions are commonly altered. Directly involved in metabolic reprogramming, mitochondrial plasticity confers to cancer cells a high degree of adaptability to a wide range ...of stresses and to the harsh tumor microenvironment. Lack of nutrients or oxygen caused by altered perfusion, metabolic needs of proliferating cells, co-option of the microenvironment, control of the immune system, cell migration and metastasis, and evasion of exogenous stress (e.g., chemotherapy) are all, at least in part, influenced by mitochondria. Mitochondria are undoubtedly one of the key contributors to cancer development and progression. Understanding their protumoral (dys)functions may pave the way to therapeutic strategies capable of turning them into innocent entities. Here, we will focus on the production and detoxification of mitochondrial reactive oxygen species (mtROS), on their impact on tumorigenesis (genetic, prosurvival, and microenvironmental effects and their involvement in autophagy), and on tumor metastasis. We will also summarize the latest therapeutic approaches involving mtROS.
Glioblastoma represents the highest grade of brain tumors. Despite maximal resection surgery associated with radiotherapy and concomitant followed by adjuvant chemotherapy with temozolomide (TMZ), ...patients have a very poor prognosis due to the rapid recurrence and the acquisition of resistance to TMZ. Here, initially considering that TMZ is a prodrug whose activation is pH-dependent, we explored the contribution of glioblastoma cell metabolism to TMZ resistance. Using isogenic TMZ-sensitive and TMZ-resistant human glioblastoma cells, we report that the expression of O6-methylguanine DNA methyltransferase (MGMT), which is known to repair TMZ-induced DNA methylation, does not primarily account for TMZ resistance. Rather, fitter mitochondria in TMZ-resistant glioblastoma cells are a direct cause of chemoresistance that can be targeted by inhibiting oxidative phosphorylation and/or autophagy/mitophagy. Unexpectedly, we found that PARP inhibitor olaparib, but not talazoparib, is also a mitochondrial Complex I inhibitor. Hence, we propose that the anticancer activities of olaparib in glioblastoma and other cancer types combine DNA repair inhibition and impairment of cancer cell respiration.
The origin and phenomenology of the Fast Radio Burst (FRB) remains unknown despite more than a decade of efforts. Though several models have been proposed to explain the observed data, none is able ...to explain alone the variety of events so far recorded. The leading models consider magnetars as potential FRB sources. The recent detection of FRBs from the galactic magnetar SGR J1935+2154 seems to support them. Still, emission duration and energetic budget challenge all these models. Like for other classes of objects initially detected in a single band, it appeared clear that any solution to the FRB enigma could only come from a coordinated observational and theoretical effort in an as wide as possible energy band. In particular, the detection and localisation of optical/NIR or/and high-energy counterparts seemed an unavoidable starting point that could shed light on the FRB physics. Multiwavelength (MWL) search campaigns were conducted for several FRBs, in particular for repeaters. Here we summarize the observational and theoretical results and the perspectives in view of the several new sources accurately localised that will likely be identified by various radio facilities worldwide. We conclude that more dedicated MWL campaigns sensitive to the millisecond–minute timescale transients are needed to address the various aspects involved in the identification of FRB counterparts. Dedicated instrumentation could be one of the key points in this respect. In the optical/NIR band, fast photometry looks to be the only viable strategy. Additionally, small/medium size radiotelescopes co-pointing higher energies telescopes look a very interesting and cheap complementary observational strategy.
Abstract
We model the intermediate-mass black hole HLX-1, using the Hubble Space Telescope, XMM–Newton and Swift. We quantify the relative contributions of a bluer component, function of X-ray ...irradiation, and a redder component, constant and likely coming from an old stellar population. We estimate a black hole mass ${\approx } (2^{+2}_{-1}) \times 10^4 \,\mathrm{M}_{{\odot }}$, a spin parameter a/M ≈ 0.9 for moderately face-on view and a peak outburst luminosity ≈0.3 times the Eddington luminosity. We discuss the discrepancy between the characteristic sizes inferred from the short X-ray time-scale (R ∼ a few 1011 cm) and from the optical emitter ($R \sqrt{\cos \theta } \approx 2.2 \times 10^{13}$ cm). One possibility is that the optical emitter is a circumbinary disc; however, we disfavour this scenario because it would require a very small donor star. A more plausible scenario is that the disc is large but only the inner annuli are involved in the X-ray outburst. We propose that the recurrent outbursts are caused by an accretion-rate oscillation driven by wind instability in the inner disc. We argue that the system has a long-term-average accretion rate of a few per cent Eddington, just below the upper limit of the low/hard state; a wind-driven oscillation can trigger transitions to the high/soft state, with a recurrence period ∼1 yr (much longer than the binary period, which we estimate as ∼10 d). The oscillation that dominated the system in the last decade is now damped such that the accretion rate no longer reaches the level required to trigger a transition. Finally, we highlight similarities between disc winds in HLX-1 and in the Galactic black hole V404 Cyg.
We present a theoretical study on the nature of the ultraluminous X-ray source NGC 1313 X-2. We evolved a set of binaries with high-mass donor stars orbiting a 20 M⊙ or a 50–100 M⊙ black hole (BH). ...Using constraints from optical observations, we restricted the candidate binary system for NGC 1313 X-2 to be either a 50–100 M⊙ BH accreting from a 12–15 M⊙ main-sequence star or a ∼20 M⊙ BH with a 12–15 M⊙ giant donor. If the modulation of 6.12 ± 0.16 d recently identified as the orbital period of the system is confirmed, a ∼20 M⊙ BH model becomes unlikely and we are left with the only possibility that the compact accretor in NGC 1313 X-2 is a massive BH of ∼50–100 M⊙.
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