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Publication . Costa, Ana Raquel Ferreira da; Santos, Cecília Reis Alves dos; Gonçalves, Isabel Maria Theriaga Mendes Varanda

In mammals, taste perception is a primordial function triggered by food ingestion which is transduced as bitter, sweet, sour, salty or umami flavours to the central nervous system. Taste receptors belong to the G protein coupled receptors superfamily and correspond to transmembrane proteins that can be divided into type 1 and type 2. There are 3 type 1 receptor subunits (TAS1Rs) that mediate sweet and umami tastes through the heterodimers TAS1R2+TAS1R3 and TAS1R1+TAS1R3, respectively. On the other hand, the group of type 2 receptors (TAS2Rs) consists of 25 members that mediate bitter taste. Although initially found in the taste buds of the oral cavity, the expression of taste receptors has been reported in several other extraoral organs and also in several types of cancer, where their function has been associated with important biological functions, such as cellular proliferation, apoptosis, glucose metabolism regulation, among others. Glioblastoma is a grade 4 brain tumour, according to the World Health Organization classification, due to its aggressiveness, invasiveness, and poor differentiation. The standard treatment for glioblastoma is surgical resection, followed by radio- and chemotherapy with temozolomide. However, the recurrence of this type of tumour is still very high, not only due to the high proliferation and infiltration of cancer cells, but also to the existence of the blood-brain barrier and hypoxic microenvironment, and to the high radio- and chemotherapy resistance. Overall, all these factors contribute to the poor prognosis of patients with glioblastoma. One of the chemoresistant mechanisms is associated with the overexpression of efflux transporters, that can be regulated by TAS2Rs. On the other hand, the metabolic reprogramming of cancer cells, known as Warburg effect, is also associated with chemoresistance and worse prognosis. Interestingly, the sweet taste receptor (STR) is an important sensor of the glucose availability and glucose metabolism in several cells and organs. Since TAS2Rs are activated by bitter tasting compounds, including several anticancer drugs, these receptors could be used as new therapeutic targets for glioblastoma. In addition, the STR inhibition could trigger the Warburg effect reversal in glioblastoma cells, as it may deceive the cells that there is no glucose available, leading to their death by starvation. Thus, the work developed during this doctoral thesis aimed at analysing the expression and function of taste receptors, particularly bitter and sweet taste receptors, in three glioblastoma cell lines. The therapeutic potential of these 2 types of taste receptor in glioblastoma was also analysed. In the first research work, we aimed to characterize the functional relevance of bitter taste receptors to be used as new therapeutic targets for glioblastoma. We firstly identified the presence of 19 TAS2Rs transcripts in glioblastoma cell lines and in a human astrocytes cell line. Differences in gene and protein expression of 4 TAS2Rs were also addressed. Moreover, the TAS2Rs expression in human tumour samples of glioblastoma was also validated. Most importantly, we also showed that the anticancer effects of temozolomide in glioblastoma cells is partially mediated by TAS2Rs activation, particularly by TAS2R43. In the second part of the research work presented in this doctoral thesis, the functional relevance of the sweet taste receptor in the glucose metabolism of glioblastoma cells was investigated. We proceeded to the identification and analysis of the 2 STR subunits expression in glioblastoma cell lines and human samples. Then, it was observed that the STR inhibition with lactisole, a TAS1R3 subunit inhibitor, reduced the viability and migration of glioblastoma cells, particularly under glucose/oxygen deprivation conditions, by limiting the glucose uptake by glioblastoma cells. Altogether, the results presented in this doctoral thesis provided evidence for the potential of bitter and sweet taste receptors as possible targets for glioblastoma treatment, to improve the prognosis of this devastating disease.

2023-04Doctoral thesis

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