The antioxidant mitochondrial protein UCP2 promotes cancer development connecting theWarburg effect and autophagy

Mitochondrial anion transporter proteins localized into the mitochondrial inner membrane. Currently, five UCP family members have been identified in mammals.Among them, UCP2 is widely distributedthroughout the organism, suggesting different and wide functions for this mitochondrial uncoupling protein. Basically, the antioxidant role of UCP2 is due to its capability to decrease the mitochondrial potential and to dissipate the proton gradient

Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells

The TP53 tumor suppressor gene is the most frequently altered gene in tumors and an increasing number of studies highlight that mutant p53 proteins can acquire oncogenic properties, referred to as gain-of-function (GOF). Reactive oxygen species (ROS) play critical roles as intracellular messengers, regulating numerous signaling pathways linked to metabolism and cell growth. Tumor cells frequently display higher ROS levels compared to healthy cells as a result of their increased metabolism as well as serving as an oncogenic agent because of its damaging and mutational properties. Several studies reported that in contrast with the wild type protein, mutant p53 isoforms fail to exert antioxidant activities and rather increase intracellular ROS, driving a pro-tumorigenic survival. These pro-oxidant oncogenic abilities of GOF mutant p53 include signaling and metabolic rewiring, as well as the modulation of critical ROS-related transcription factors and antioxidant systems, which lead ROS unbalance linked to tumor progression. The studies summarized here highlight that GOF mutant p53 isoforms might constitute major targets for selective therapeutic intervention against several types of tumors and that ROS enhancement driven by mutant p53 might represent an "Achilles heel" of cancer cells, suggesting pro-oxidant drugs as a therapeutic approach for cancer patients bearing the mutant TP53 gene

Medications prescriptions in COVID-19 pregnant and lactating women: the Bergamo Teratology Information Service experience during COVID-19 outbreak in Italy

Abstract Objectives The severe acute respiratory syndrome coronavirus 2 (COVID-19) outbreak in Italy, especially in Lombardy and Bergamo city, represented probably nowadays one of the first major clusters of COVID-19 in the world. The aim of this report is to describe the activity of Bergamo Teratology Information Service (TIS) in supporting the public and health-care personnel in case of drug prescriptions in suspected/confirmed COVID-19 pregnant and lactating patients during COVID-19 outbreak in Italy. Methods All Bergamo TIS requests concerning COVID-19 pregnant and lactating women have been retrospectively evaluated from 1 March to 15 April 2020. Type of medications, drug's safety profile and compatibility with pregnancy and lactation are reported. Results Our service received information calls concerning 48 (9 pregnant, 35 lactating) patients. Among pregnant and lactating women, the requests of information were related to 16 and 60 drugs prescriptions respectively. More than half concerned drugs prescriptions during the first and second trimester (13/16) and during the first six months of lactation (37/60). Hydroxychloroquine and azithromycin were the most involved. Conclusions Hydroxychloroquine and azithromycin at dosages used for COVID-19 may be considered compatible and reasonably safe either in pregnancy and lactation. Antivirals may be considered acceptable in pregnancy. During lactation lopinavir and ritonavir probably exhibit some supportive data from literature that darunavir and cobicistat do not. Tocilizumab may be considered for COVID-19 treatment because no increased malformation rate were observed until now. However caution may be advised because human data are limited and the potential risk of embryo-fetal toxicity cannot be excluded

Tumor Suppressor Role of Wild-Type P53-Dependent Secretome and Its Proteomic Identification in PDAC

: The study of the cancer secretome is gaining even more importance in cancers such as pancreatic ductal adenocarcinoma (PDAC), whose lack of recognizable symptoms and early detection assays make this type of cancer highly lethal. The wild-type p53 protein, frequently mutated in PDAC, prevents tumorigenesis by regulating a plethora of signaling pathways. The importance of the p53 tumor suppressive activity is not only primarily involved within cells to limit tumor cell proliferation but also in the extracellular space. Thus, loss of p53 has a profound impact on the secretome composition of cancer cells and marks the transition to invasiveness. Here, we demonstrate the tumor suppressive role of wild-type p53 on cancer cell secretome, showing the anti-proliferative, apoptotic and chemosensitivity effects of wild-type p53 driven conditioned medium. By using high-resolution SWATH-MS technology, we characterized the secretomes of p53-deficient and p53-expressing PDAC cells. We found a great number of secreted proteins that have known roles in cancer-related processes, 30 of which showed enhanced and 17 reduced secretion in response to p53 silencing. These results are important to advance our understanding on the link between wt-p53 and cancer microenvironment. In conclusion, this approach may detect a secreted signature specifically driven by wild-type p53 in PDAC

Autocrine mechanisms of cancer chemoresistance

An ever-increasing number of studies highlight the role of cancer secretome in the modification of tumour microenvironment and in the acquisition of cancer cell resistance to therapeutic drugs. The knowledge of the mechanisms underlying the relationship between cancer cell-secreted factors and chemoresistance is becoming fundamental for the identification of novel anticancer therapeutic strategies overcoming drug resistance and novel prognostic secreted biomarkers. In this review, we summarize the novel findings concerning the regulation of secreted molecules by cancer cells compromising drug sensitivity. In particular, we highlight data from available literature describing the involvement of cancer cell-secreted molecules determining chemoresistance in an autocrine manner, including: i) growth factors; ii) glycoproteins; iii) inflammatory cytokines; iv) enzymes and chaperones; and v) tumor-derived exosomes

Molecular interplay between mutant p53 proteins and autophagy in cancer cells

An increasing number of studies highlight the role of mutant p53 proteins in cancer cell growth and in the worsening of cancer patients' clinical outcome. Autophagy has been widely recognized as a main biological event involved in both the regulation of cancer cell proliferation and in the response of several anticancer drugs. A thorough analysis of scientific literature underlines the reciprocal interplay between mutant p53 proteins and autophagy regulation. In this review, we analytically summarize recent findings, which indicate that gain-of-function (GOF) mutant p53 proteins counteract the autophagic machinery by various molecular mechanisms including the regulation of AMPK and Akt/mTOR pathways, autophagy-related genes (ATGs), HIF-1α target genes, and the mitochondrial citrate carrier CIC. Moreover, we report that mutant p53 protein stability is affected by lysosome-mediated degradation through macroautophagy or chaperone-mediated autophagy, suggesting the use of autophagy stimulators to counteract mutant p53 oncogenic activity. Finally, we discuss the functional role of the interplay between mutant p53 proteins and autophagy in cancer progression, a fundamental knowledge to design more effective therapies against cancers bearing mutant TP53 gene

Redox sensitive cysteine residues as crucial regulators of wild-type and mutant p53 isoforms

: The wild-type protein p53 plays a key role in preventing the formation of neoplasms by controlling cell growth. However, in more than a half of all cancers, the TP53 gene has missense mutations that appear during tumorigenesis. In most cases, the mutated gene encodes a full-length protein with the substitution of a single amino acid, resulting in structural and functional changes and acquiring an oncogenic role. This dual role of the wild-type protein and the mutated isoforms is also evident in the regulation of the redox state of the cell, with antioxidant and prooxidant functions, respectively. In this review, we introduce a new concept of the p53 protein by discussing its sensitivity to the cellular redox state. In particular, we focus on the discussion of structural and functional changes following post-translational modifications of redox-sensitive cysteine residues, which are also responsible for interacting with zinc ions for proper structural folding. We will also discuss therapeutic opportunities using small molecules targeting cysteines capable of modifying the structure and function of the p53 mutant isoforms in view of possible anticancer therapies for patients possessing the mutation in the TP53 gene

Long-Acting Injectable Antipsychotic Treatment during Pregnancy: A Case Series

Introduction: Data from the literature show that prolonged-release injectable antipsychotics (LAIs) ensure constant blood drug levels better patient compliance and offer a simpler treatment regimen for both patients and caregivers. This observational–descriptive study aims to detect the possible complications found in newborns of women with bipolar or psychotic disorders and LAI therapy during pregnancy. Methods: This study involved women with psychotic disorders during pregnancy who contacted the Teratology Information Center of Bergamo, Italy between 2016 and 2021 to receive counseling on the possible risks of exposure to LAI therapy. The follow-up procedure was carried out by telephone interview or direct contact with the patient and/or her physician. Results: In this study, LAI treatment in pregnancy was not associated with an increased risk of malformations. All but one of the children in the sample were born healthy and the mothers maintained psychopathological compensation during pregnancy. Conclusions: This study showed that, despite the small size of the sample under examination, the administration of LAIs do not compromise the normal intrauterine development of the unborn child and there were no evident major malformations

Mutant p53 proteins alter cancer cell secretome and tumour microenvironment: involvement in cancer invasion and metastasis

An ever-increasing number of studies highlight the role of mutant p53 proteins in the alteration of cancer cell secretome and in the modification of tumour microenvironment, sustaining an invasive phenotype of cancer cell. The knowledge of the molecular mechanisms underlying the interplay between mutant p53 proteins and the microenvironment is becoming fundamental for the identification of both efficient anticancer therapeutic strategies and novel serum biomarkers. In this review, we summarize the novel findings concerning the regulation of secreted molecules by cancer cells bearing mutant TP53 gene. In particular, we highlight data from available literature suggesting that mutant p53 proteins are able to : i) alter the secretion of enzymes involved in the modulation of extracellular matrix components; ii) alter the secretion of inflammatory cytokines; iii) increase the extracellular acidification; and iv) regulate the crosstalk between cancer and stromal cells