LonP1 Differently Modulates Mitochondrial Function and Bioenergetics of Primary Versus Metastatic Colon Cancer Cells

Gibellini, Lara; Losi, Lorena; Biasi, Sara De; Nasi, Milena; Tartaro, Domenico Lo; Pecorini, Simone; Patergnani, Simone; Pinton, Paolo; Gaetano, Anna De; Carnevale, Gianluca; Pisciotta, Alessandra; Mariani, Francesco; Roncucci, Luca; Iannone, Anna; Cossarizza, Andrea

doi:10.3389/fonc.2018.00254

Cited by 48 publications

(52 citation statements)

References 38 publications

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“…This effect is due, at least in part, to the inhibition of Lonp1 functions, since the expression of this enzyme is not significantly altered by CDDO and CDDO-Me, but the levels of Lonp1 enzymatic activity targets, such as aconitase or TFAM, significantly increase. In line with these observations, Lonp1 overexpression abrogates the effects of CDDO and CDDO-Me, protecting cells from apoptosis [97,98].…”

Section: Anticancer Effects Of Triterpenoidsmentioning

confidence: 81%

Synthesis and Anticancer Activity of CDDO and CDDO-Me, Two Derivatives of Natural Triterpenoids

et al. 2019

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Triterpenoids are natural compounds synthesized by plants through cyclization of squalene, known for their weak anti-inflammatory activity. 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), and its C28 modified derivative, methyl-ester (CDDO-Me, also known as bardoxolone methyl), are two synthetic derivatives of oleanolic acid, synthesized more than 20 years ago, in an attempt to enhance the anti-inflammatory behavior of the natural compound. These molecules have been extensively investigated for their strong ability to exert antiproliferative, antiangiogenic, and antimetastatic activities, and to induce apoptosis and differentiation in cancer cells. Here, we discuss the chemical properties of natural triterpenoids, the pathways of synthesis and the biological effects of CDDO and its derivative CDDO-Me. At nanomolar doses, CDDO and CDDO-Me have been shown to protect cells and tissues from oxidative stress by increasing the transcriptional activity of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2). At doses higher than 100 nM, CDDO and CDDO-Me are able to modulate the differentiation of a variety of cell types, both tumor cell lines or primary culture cell, while at micromolar doses these compounds exert an anticancer effect in multiple manners; by inducing extrinsic or intrinsic apoptotic pathways, or autophagic cell death, by inhibiting telomerase activity, by disrupting mitochondrial functions through Lon protease inhibition, and by blocking the deubiquitylating enzyme USP7. CDDO-Me demonstrated its efficacy as anticancer drugs in different mouse models, and versus several types of cancer. Several clinical trials have been started in humans for evaluating CDDO-Me efficacy as anticancer and anti-inflammatory drug; despite promising results, significant increase in heart failure events represented an obstacle for the clinical use of CDDO-Me.

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Section: Anticancer Effects Of Triterpenoidsmentioning

confidence: 81%

Synthesis and Anticancer Activity of CDDO and CDDO-Me, Two Derivatives of Natural Triterpenoids

et al. 2019

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“…This cluster was chosen because there were sufficient leading edge genes to permit this type of analysis. IPA predicted regulators of the metabolism cluster include modulators of metabolic transitions to aerobic glycolysis (PCGEM1, 72 LONP1 73 and TRAP1 74 ), as well as established mediators of effector cell sustained respiratory capacity (SRC), Il-15. 75 Finally we examined the genome plot of our ATAC-seq data at the Xbp1 locus to assess for DARs at this gene.…”

Section: Resultsmentioning

confidence: 99%

Influenza-specific effector memory B cells predict long-lived antibody responses to vaccination in humans

Nellore

Zumaquero

et al. 2019

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Early surrogates for long-lived immunity after inactivated influenza vaccination (IIV) are lacking. Antigen-specific memory B cells (Bmem) after IIV have been recently identified. We show that the antigen-specific Bmem compartment after IIV is heterogenous and comprises a clonotypically and transcriptionally distinct T-bethi subset that persists in circulation over time after vaccination and exclusively correlates with the long-lived antibody response. We demonstrate that this subset has an effector memory transcriptome and is epigenetically remodeled to facilitate intracellular immunoglobulin production. Finally, via clonal sharing, we show an enriched in vivo ontologic relationship between the secondary plasmablast response that develops after vaccine boost and the T-bethi fraction of the flu-specific Bmem response that forms after initial prime. Collectively, our data identify a novel biomarker of durable humoral immunity after influenza vaccination.

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“…OCR was quantified at the beginning of the assay and after the sequential injection of 2 μM oligomycin, 0.5 μM Carbonyl cyanide‐4‐(trifluoromethoxy)phenylhydrazone (FCCP) and 0.5 μM of rotenone plus antimycin A (all from reagents Mito Stress Test kit, Agilent Technologies). Respiratory parameters were obtained as indicated: basal respiration as baseline OCR; proton leak by subtracting OCR after oligomycin injection to basal OCR; ATP‐linked respiration by subtracting the proton leak to the basal OCR; spare respiratory capacity as the difference between the maximal respiration and the basal respiration; maximal OCR by calculating the difference of antimycin plus rotenone rate from FCCP rate (Gibellini et al , 2018; De Biasi et al , 2019). The capacity of cells to maintain the maximal respiration was determined by assaying the area under the curve (AUC) from the sixth to tenth measurement.…”

Section: Methodsmentioning

confidence: 99%

Altered bioenergetics and mitochondrial dysfunction of monocytes in patients with COVID‐19 pneumonia

et al. 2020

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In patients infected by SARS-CoV-2 who experience an exaggerated inflammation leading to pneumonia, monocytes likely play a major role but have received poor attention. Thus, we analyzed peripheral blood monocytes from patients with COVID-19 pneumonia and found that these cells show signs of altered bioenergetics and mitochondrial dysfunction, had a reduced basal and maximal respiration, reduced spare respiratory capacity, and decreased proton leak. Basal extracellular acidification rate was also diminished, suggesting reduced capability to perform aerobic glycolysis. Although COVID-19 monocytes had a reduced ability to perform oxidative burst, they were still capable of producing TNF and IFN-c in vitro. A significantly high amount of monocytes had depolarized mitochondria and abnormal mitochondrial ultrastructure. A redistribution of monocyte subsets, with a significant expansion of intermediate/pro-inflammatory cells, and high amounts of immature monocytes were found, along with a concomitant compression of classical monocytes, and an increased expression of inhibitory checkpoints like PD-1/PD-L1. High plasma levels of several inflammatory cytokines and chemokines, including GM-CSF, IL-18, CCL2, CXCL10, and osteopontin, finally confirm the importance of monocytes in COVID-19 immunopathogenesis.

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LonP1 Differently Modulates Mitochondrial Function and Bioenergetics of Primary Versus Metastatic Colon Cancer Cells

Cited by 48 publications

References 38 publications

Synthesis and Anticancer Activity of CDDO and CDDO-Me, Two Derivatives of Natural Triterpenoids

Synthesis and Anticancer Activity of CDDO and CDDO-Me, Two Derivatives of Natural Triterpenoids

Influenza-specific effector memory B cells predict long-lived antibody responses to vaccination in humans

Altered bioenergetics and mitochondrial dysfunction of monocytes in patients with COVID‐19 pneumonia

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