Hormones and immunity in cancer: are thyroid hormones endocrine players in the microglia/glioma cross-talk?

Perrotta, Cristiana; Palma, Clara De; Clementi, Emilio; Cervia, Davide

doi:10.3389/fncel.2015.00236

Cited by 15 publications

(12 citation statements)

References 78 publications

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“…The molecular mechanism involves T3 uptake by TH transporters and binding to TRs, thus triggering multiple signaling pathways (80, 81). Moreover, T3 increased the release of soluble factors by the microglia through STAT3 activation, promoting glioma growth (82).…”

Section: Introductionmentioning

confidence: 99%

Thyroid Hormone Action on Innate Immunity

2019

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The interplay between thyroid hormone action and the immune system has been established in physiological and pathological settings. However, their connection is complex and still not completely understood. The thyroid hormones (THs), 3,3′,5,5′ tetraiodo-L-thyroxine (T4) and 3,3′,5-triiodo-L-thyronine (T3) play essential roles in both the innate and adaptive immune responses. Despite much research having been carried out on this topic, the available data are sometimes difficult to interpret or even contradictory. Innate immune cells act as the first line of defense, mainly involving granulocytes and natural killer cells. In turn, antigen presenting cells, macrophages and dendritic cells capture, process and present antigens (self and foreign) to naïve T lymphocytes in secondary lymphoid tissues for the development of adaptive immunity. Here, we review the cellular and molecular mechanisms involved in T4 and T3 effects on innate immune cells. An overview of the state-of-the-art of TH transport across the target cell membrane, TH metabolism inside these cells, and the genomic and non-genomic mechanisms involved in the action of THs in the different innate immune cell subsets is included. The present knowledge of TH effects as well as the thyroid status on innate immunity helps to understand the complex adaptive responses achieved with profound implications in immunopathology, which include inflammation, cancer and autoimmunity, at the crossroads of the immune and endocrine systems.

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Section: Introductionmentioning

confidence: 99%

Thyroid Hormone Action on Innate Immunity

2019

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“…Using published protocols 18,23,54,62,75,76 , in vivo resected B16-F10 tumours and human or murine cancer cell lines were homogenised in RIPA lysis buffer, supplemented with a cocktail of protease and phosphatase inhibitors (cOmplete and PhosSTOP; Roche Diagnostics, Milano, Italy). Equal amounts of proteins were separated by 4–20% SDS-polyacrylamide gel electrophoresis (Criterion TGX Stain-free precast gels and Criterion Cell system; Bio-Rad) and transferred onto nitrocellulose membrane using a Bio-Rad Trans-Blot Turbo System.…”

Section: Methodsmentioning

confidence: 99%

Dysfunctional autophagy induced by the pro-apoptotic natural compound climacostol in tumour cells

et al. 2018

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Autophagy occurs at a basal level in all eukaryotic cells and may support cell survival or activate death pathways. Due to its pathophysiologic significance, the autophagic machinery is a promising target for the development of multiple approaches for anti-neoplastic agents. We have recently described the cytotoxic and pro-apoptotic mechanisms, targeting the tumour suppressor p53, of climacostol, a natural product of the ciliated protozoan Climacostomum virens. We report here on how climacostol regulates autophagy and the involvement of p53-dependent mechanisms. Using both in vitro and in vivo techniques, we show that climacostol potently and selectively impairs autophagy in multiple tumour cells that are committed to die by apoptosis. In particular, in B16-F10 mouse melanomas climacostol exerts a marked and sustained accumulation of autophagosomes as the result of dysfunctional autophagic degradation. We also provide mechanistic insights showing that climacostol affects autophagosome turnover via p53-AMPK axis, although the mTOR pathway unrelated to p53 levels plays a role. In particular, climacostol activated p53 inducing the upregulation of p53 protein levels in the nuclei through effects on p53 stability at translational level, as for instance the phosphorylation at Ser15 site. Noteworthy, AMPKα activation was the major responsible of climacostol-induced autophagy disruption in the absence of a key role regulating cell death, thus indicating that climacostol effects on autophagy and apoptosis are two separate events, which may act independently on life/death decisions of the cell. Since the activation of p53 system is at the molecular crossroad regulating both the anti-autophagic action of climacostol and its role in the apoptosis induction, it might be important to explore the dual targeting of autophagy and apoptosis with agents acting on p53 for the selective killing of tumours. These findings also suggest the efficacy of ciliate bioactive molecules to identify novel lead compounds in drug discovery and development.

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“…Using published protocols (Perrotta et al, 2015, 2018; Catalani et al, 2016), cells were homogenized in RIPA lysis buffer, supplemented with a cocktail of protease inhibitors (cOmplete; Roche Diagnostics, Milano, Italy). Equal amounts of proteins were separated by 4–20% SDS-polyacrylamide gel electrophoresis (Criterion TGX Stain-free precast gels and Criterion Cell system; Bio-Rad, Hercules, CA, USA) and transferred onto nitrocellulose membrane using a Bio-Rad Trans-Blot Turbo System.…”

Section: Methodsmentioning

confidence: 99%

The Natural Compound Climacostol as a Prodrug Strategy Based on pH Activation for Efficient Delivery of Cytotoxic Small Agents

et al. 2019

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We synthesized and characterized MOMO as a new small molecule analog of the cytotoxic natural product climacostol efficiently activated in mild extracellular acidosis. The synthesis of MOMO had a key step in the Wittig olefination for the construction of the carbon-carbon double bond in the alkenyl moiety of climacostol. The possibility of obtaining the target ( Z )-alkenyl MOMO derivative in very good yield and without presence of the less active ( E )-diastereomer was favored from the methoxymethyl ether (MOM)-protecting group of hydroxyl functions in aromatic ring of climacostol aldehyde intermediate. Of interest, the easy removal of MOM-protecting group in a weakly acidic environment allowed us to obtain a great quantity of climacostol in biologically active (Z)-configuration. Results obtained in free-living ciliates that share the same micro-environment of the climacostol natural producer Climacostomum virens demonstrated that MOMO is well-tolerated in a physiological environment, while its cytotoxicity is rapidly and efficiently triggered at pH 6.3. In addition, the cytostatic vs. cytotoxic effects of acidified-MOMO can be modulated in a dose-dependent manner. In mouse melanoma cells, MOMO displayed a marked pH-sensitivity since its cytotoxic and apoptotic effects become evident only in mild extracellular acidosis. Data also suggested MOMO being preferentially activated in the unique extra-acidic microenvironment that characterizes tumoural cells. Finally, the use of the model organism Drosophila melanogaster fed with an acidic diet supported the efficient activity and oral delivery of MOMO molecule in vivo . MOMO affected oviposition of mating adults and larvae eclosion. Reduced survival of flies was due to lethality during the larval stages while emerging larvae retained their ability to develop into adults. Interestingly, the gut of eclosed larvae exhibited an extended damage (cell death by apoptosis) and the brain tissue was also affected (reduced mitosis), demonstrating that orally activated MOMO efficiently targets different tissues of the developing fly. These results provided a proof-of-concept study on the pH-dependence of MOMO effects. In this respect, MOM-protection emerges as a potential prodrug strategy which deserves to be further investigated for the generation of efficient pH-sensitive small organic molecules as pharmacologically active cytotoxic compounds.

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Hormones and immunity in cancer: are thyroid hormones endocrine players in the microglia/glioma cross-talk?

Cited by 15 publications

References 78 publications

Thyroid Hormone Action on Innate Immunity

Thyroid Hormone Action on Innate Immunity

Dysfunctional autophagy induced by the pro-apoptotic natural compound climacostol in tumour cells

The Natural Compound Climacostol as a Prodrug Strategy Based on pH Activation for Efficient Delivery of Cytotoxic Small Agents

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