Browsing by Author "Lima, Raquel T."
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- Assessing the antitumor potential of variants of the extracellular carbohydrate polymer from synechocystis ΔsigF mutantPublication . Mota, Rita; Lima, Raquel T.; Flores, Carlos; Silva, Juliana F.; Cruz, Beatriz; Alves, Bárbara; Pinto, Marta T.; Adessi, Alessandra; Pereira, Sara B.; De Philippis, Roberto; Soares, Paula; Tamagnini, PaulaCancer is a leading cause of death worldwide with a huge societal and economic impact. Clinically effective and less expensive anticancer agents derived from natural sources can help to overcome limitations and negative side effects of chemotherapy and radiotherapy. Previously, we showed that the extracellular carbohydrate polymer of a Synechocystis ΔsigF overproducing mutant displayed a strong antitumor activity towards several human tumor cell lines, by inducing high levels of apoptosis through p53 and caspase-3 activation. Here, the ΔsigF polymer was manipulated to obtain variants that were tested in a human melanoma (Mewo) cell line. Our results demonstrated that high molecular mass fractions were important for the polymer bioactivity, and that the reduction of the peptide content generated a variant with enhanced in vitro antitumor activity. This variant, and the original ΔsigF polymer, were further tested in vivo using the chick chorioallantoic membrane (CAM) assay. Both polymers significantly decreased xenografted CAM tumor growth and affected tumor morphology, by promoting less compact tumors, validating their antitumor potential in vivo. This work contributes with strategies for the design and testing tailored cyanobacterial extracellular polymers and further strengths the relevance of evaluating this type of polymers for biotechnological/biomedical applications.
- High VEGFA expression Is associated with improved progression-free survival after Bevacizumab treatment in recurrent GlioblastomaPublication . Alves, Bárbara; Peixoto, Joana; Macedo, Sofia; Pinheiro, Jorge; Carvalho, Bruno; Soares, Paula; Lima, Jorge; Lima, Raquel T.Glioblastoma (GB) is a deadly tumor that demands for relevant biomarkers, particularly regarding patients’ response to treatment. MMP-2, MMP-9, VEGFA, and YKL40 are important molecules, given their implication in the infiltrative and angiogenic phenotype of GBs. The purpose of this study was to assess the relationship between the expression of MMP-2, MMP-9, VEGFA, and YKL40 in GB tissues and the patients’ response to temozolomide (first-line treatment) or bevacizumab (second-line treatment). Our results showed that increased VEGFA is significantly associated with an improved response to bevacizumab, while having no correlation with the response to temozolomide. Additionally, YKL40 expression may also be important regarding information about the extent of antiangiogenic treatment in GB patients.
- Targeting mitochondrial TERT to overcome therapeutic resistancePublication . Chantre, Ana; Correia, Marcelo; Soares, Paula; Máximo, Valdemar; Lima, Raquel T.Reactivation of telomerase is a common process in most human tumours [1, 2], usually due to reexpression of its catalytic subunit, the telomerase reverse transcriptase (TERT), contributing to cell immortalization [3]. In thyroid cancer (TC), it was demonstrated that TERT reactivation is often associated with distant metastases, therapy resistance and shorter survival rates of patients [4], however TERTs’ canonical functions are not enough to explain these clinical associations. Some works have been proposing a possible non-canonical function of TERT, specifically in mitochondria, as it can translocate into this organelle due to the presence of a N-terminal target mitochondrial sequence (MTS) [1]. In mitochondria, TERT seems to contribute to: protection of mtDNA under oxidative stress; decrease in the production of ROS and apoptosis; increase in mitochondrial membrane potential; and improvement of cellular respiration [5]. Our hypothesis is that the translocation of TERT into mitochondria, in TC cells, may indicate a mechanism of response to oxidative stress caused by cancer therapeutics. Therefore, in this project we are evaluating TERTs’ impact in mitochondria in a CRISPR-Cas9 altered TC cell line which lacks the MTS region of TERT (preventing its translocation into this organelle) in comparison with control cells. Currently, we are characterizing the altered cells regarding cell growth and viability (Trypan Blue Exclusion and PrestoBlue Assays), cell cycle profile and proliferation (Flow Cytometry with PI, BrdU Incorporation Asssay). We will further evaluate the effects of these alterations in mitochondrial functions, namely oxidative stress (specific dyes), apoptosis (Flow Cytometry with Annexin V/PI), and metabolism (Seahorse Analyser) as well as in the cellular response to therapeutic drugs. Overall, this study will allow to evaluate the relevance of mitochondrial TERT-related functions as they might contribute to the discovery of novel targets and therapeutic opportunities for TC patients.