42 research outputs found
PGC1α: Friend or Foe in Cancer?
No full textThe PGC1 family (Peroxisome proliferator-activated receptor Î3 (PPAR Î3) coactivators) of transcriptional coactivators are considered master regulators of mitochondrial biogenesis and function. The PGC1α isoform is expressed especially in metabolically active tissues, such as the liver, kidneys and brain, and responds to energy-demanding situations. Given the altered and highly adaptable metabolism of tumor cells, it is of interest to investigate PGC1α in cancer. Both high and low levels of PGC1α expression have been reported to be associated with cancer and worse prognosis, and PGC1α has been attributed with oncogenic as well as tumor suppressive features. Early in carcinogenesis PGC1α may be downregulated due to a protective anticancer role, and low levels likely reflect a glycolytic phenotype. We suggest mechanisms of PGC1α downregulation and how these might be connected to the increased cancer risk that obesity is now known to entail. Later in tumor progression PGC1α is often upregulated and is reported to contribute to increased lipid and fatty acid metabolism and/or a tumor cell phenotype with an overall metabolic plasticity that likely supports drug resistance as well as metastasis. We conclude that in cancer PGC1α is neither friend nor foe, but rather the obedient servant reacting to metabolic and environmental cues to benefit the tumor cell
The α-ketoglutarate dehydrogenase complex in cancer metabolic plasticity
No full textDeregulated metabolism is a well-established hallmark of cancer. At the hub of various metabolic pathways deeply integrated within mitochondrial functions, the α-ketoglutarate dehydrogenase complex represents a major modulator of electron transport chain activity and tricarboxylic acid cycle (TCA) flux, and is a pivotal enzyme in the metabolic reprogramming following a cancer cell’s change in bioenergetic requirements. By contributing to the control of α-ketoglutarate levels, dynamics, and oxidation state, the α-ketoglutarate dehydrogenase is also essential in modulating the epigenetic landscape of cancer cells. In this review, we will discuss the manifold roles that this TCA enzyme and its substrate play in cancer
Mitochondrial Mutations in Cancer Progression: Causative, Bystanders, or Modifiers of Tumorigenesis?
No full textMitochondrial DNA encodes genes that are de facto metabolic enzymes and are currently emerging as pivotal players in the origin, progression, and outcome of human cancers. We here revise the multifaceted implications of mitochondrial mutations on the metabolic reprogramming cancer cells must undergo to adapt and proliferate. The sources of such mutations and the processes that govern their positive selection are described, along with the consequences that a deranged respiratory metabolism may have on the remodeling that follows oncogenes activation or tumor suppressors ablation. Ultimately, we dwell on the peculiar features of oncocytic tumors, one of the most relevant yet mysterious models to functionally investigate the role of mitochondrial mutations in cancer
A multi-parametric workflow for the prioritization of mitochondrial DNA variants of clinical interest
No full textAssigning a pathogenic role to mitochondrial DNA (mtDNA) variants and unveiling the potential involvement of the mitochondrial genome in diseases are challenging tasks in human medicine. Assuming that rare variants are more likely to be damaging, we designed a phylogeny-based prioritization workflow to obtain a reliable pool of candidate variants for further investigations. The prioritization workflow relies on an exhaustive functional annotation through the mtDNA extraction pipeline MToolBox and includes Macro Haplogroup Consensus Sequences to filter out fixed evolutionary variants and report rare or private variants, the nucleotide variability as reported in HmtDB and the disease score based on several predictors of pathogenicity for non-synonymous variants. Cutoffs for both the disease score as well as for the nucleotide variability index were established with the aim to discriminate sequence variants contributing to defective phenotypes. The workflow was validated on mitochondrial sequences from Leber's Hereditary Optic Neuropathy affected individuals, successfully identifying 23 variants including the majority of the known causative ones. The application of the prioritization workflow to cancer datasets allowed to trim down the number of candidate for subsequent functional analyses, unveiling among these a high percentage of somatic variants. Prioritization criteria were implemented in both standalone ( http://sourceforge.net/projects/mtoolbox/ ) and web version ( https://mseqdr.org/mtoolbox.php ) of MToolBox
Molecular and metabolic features of oncocytomas: seeking the blueprints of indolent cancers
No full textOncocytic tumors are a peculiar subset of human neoplasms in which mitochondria have been proven to have a prominent role. A number of paradoxes renders these clinical entities interesting from the translational research point of view. Most oncocytic tumors are generally metabolically constrained due to the impaired respiratory capacity and lack of the ability to respond to hypoxia, yet they maintain features that allow them to strive and persist in an indolent form. Their unique molecular and metabolic characteristics are an object of investigation that may reveal novel ways for therapeutic strategies based on metabolic targeting. With this aim in mind, we here examine the current knowledge on oncocytomas and delve into the molecular causes and consequences that revolve around the oncocytic phenotype, to understand whether we can learn to design therapies from the dissection of benign neoplasms
Synergistic Effect of Mitochondrial and Lysosomal Dysfunction in Parkinson’s Disease
No full textCrosstalk between lysosomes and mitochondria plays a central role in Parkinson’s Disease (PD). Lysosomal function may be influenced by mitochondrial quality control, dynamics and/or respiration, but whether dysfunction of endocytic or autophagic pathway is associated with mitochondrial impairment determining accumulation of defective mitochondria, is not yet understood. Here, we performed live imaging, western blotting analysis, sequencing of mitochondrial DNA (mtDNA) and senescence-associated beta-galactosidase activity assay on primary fibroblasts from a young patient affected by PD, her mother and a healthy control to analyze the occurrence of mtDNA mutations, lysosomal abundance, acidification and function, mitochondrial biogenesis activation and senescence. We showed synergistic alterations in lysosomal functions and mitochondrial biogenesis, likely associated with a mitochondrial genetic defect, with a consequent block of mitochondrial turnover and occurrence of premature cellular senescence in PARK2-PD fibroblasts, suggesting that these alterations represent potential mechanisms contributing to the loss of dopaminergic neurons
Characterization of Chemoresistance in Pancreatic Cancer: A Look at MDR-1 Polymorphisms and Expression in Cancer Cells and Patients
No full textPancreatic malignancy is the fourth cause of cancer-related death in Western countries and is predicted to become the second leading cause of cancer-related mortality by 2030. The standard therapies (FOLFIRINOX and gemcitabine with nab-paclitaxel) are not resolutive because this type of cancer is also characterized by a high chemoresistance, due in part to the activity of the ATP Binding Cassette (ABC) pumps accounting for the reduction in the intracellular concentration of the drugs. In this work, we analyze the occurrence of single-nucleotide polymorphisms (SNPs) in the MDR-1 gene, in different pancreatic cancer cell lines, and in tissues from pancreatic cancer patients by DNA sequencing, as well as the expression levels of MDR-1 mRNA and protein, by qRT-PCR and Western Blot analysis. We found that gemcitabine-resistant cells, in conjunction with homozygosis of analyzed SNPs, showed high MDR-1 basal levels with further increases after gemcitabine treatment. Nevertheless, we did not observe in the human PDAC samples a correlation between the level of MDR-1 mRNA and protein expression and SNPs. Preliminary, we conclude that in our small cohort, these SNPs cannot be used as molecular markers for predicting the levels of MDR-1 mRNA/protein levels and drug responses in patients with PDAC
Induced mitochondrial deficit by NDUFS3 transient silencing reduces RAB7 expression and causes lysosomal dysfunction in pancreatic cancer cells
No full textAbstract Background RAB7 is a small GTPase with multiple cellular roles, regulating late endocytic trafficking and lysosomal biogenesis, influencing mitochondria-lysosome crosstalk, and contributing to many mitochondrial processes. Mitochondrial dysfunctions are widely reported in cancer and the development of cancer therapeutic strategies targeting mitochondria gained momentum in recent years. Mitochondrial impairment can cause alterations of mitochondria-lysosome crosstalk and can influence lysosomal function. Here, we used cell models of pancreatic cancer, one of the deadliest cancers worldwide, to cause a transient mild mitochondrial deficit lowering NDUFS3 protein levels in order to investigate the consequences on RAB7 and on the late endocytic pathway and, thus, the contribution of the mitochondria-lysosomes communication alterations to cancer progression. Methods NDUFS3 and RAB7 downregulation was obtained by RNA interference (RNAi). Seahorse assays, Western blot analysis, mitochondrial staining, and Transmission Electron Microscopy (TEM) were used to assess silencing effects on mitochondrial structure and functioning. Western blotting was used to investigate expression of late endocytic pathway proteins and of the invasion marker vimentin. Confocal microscopy was used to analyze the mitochondrial network and lysosomal assessment. Zymography was performed to evaluate the ability to digest the extracellular matrix linked to cancer migration. SRB and colony assays were performed to assess cancer viability and proliferation. Wound healing assay and FluoroBlok membranes were used to determine migration and invasiveness. Results In pancreatic cancer cells, transient silencing of the NDUFS3 protein caused mitochondrial deficit, slower oxidative metabolism, and mitochondrial morphology alterations. In this context, we observed RAB7 downregulation and impairment of the late endocytic pathway. In addition, NDUFS3-silenced RAB7-downregulated cells showed less invasive tumorigenic potential revealed by reduced levels of vimentin and other Epithelial-to-Mesenchymal Transition proteins, decreased viability, migration and invasiveness. Moreover, we found that modulation of RAB7 expression may regulate vimentin levels and influence mitochondrial morphology and levels of mitochondrial proteins. Conclusions Overall, our data show that mitochondrial deficit determines alterations of the crosstalk with lysosomes, leading to dysfunctions, and that this process is regulated by RAB7 acting as an oncogene. This highlights the synergic role of RAB7 and mitochondrial dysfunction, focusing on a cellular mechanism that may boost the effect of mitochondrial dysfunction in the cells, leading to the reduction of the tumorigenic potential
Potential for Mitochondrial DNA Sequencing in the Differential Diagnosis of Gynaecological Malignancies
No full textIn the event of multiple synchronous gynecological lesions, a fundamental piece of information to determine patient management, prognosis, and therapeutic regimen choice is whether the simultaneous malignancies arise independently or as a result of metastatic dissemination. An example of synchronous primary tumors of the female genital tract most frequently described are ovarian and endometrial cancers. Surgical findings and histopathological examination aimed at resolving this conundrum may be aided by molecular analyses, although they are too often inconclusive. High mitochondrial DNA (mtDNA) variability and its propensity to accumulate mutations has been proposed by our group as a tool to define clonality. We showed mtDNA sequencing to be informative in synchronous primary ovarian and endometrial cancer, detecting tumor-specific mutations in both lesions, ruling out independence of the two neoplasms, and indicating clonality. Furthermore, we tested this method in another frequent simultaneously detected gynecological lesion type, borderline ovarian cancer and their peritoneal implants, which may be monoclonal extra-ovarian metastases or polyclonal independent masses. The purpose of this review is to provide an update on the potential use of mtDNA sequencing in distinguishing independent and metastatic lesions in gynecological cancers, and to compare the efficiency of molecular analyses currently in use with this novel method
Ovarian Neuroendocrine Tumors: Pathological and Immunohistochemical Features of a Single- Center Case Series
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