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1.
Isoforms of autophagy-related proteins: role in glioma progression and therapy resistance.
Belyaeva, E, Kharwar, RK, Ulasov, IV, Karlina, I, Timashev, P, Mohammadinejad, R, Acharya, A
Molecular and cellular biochemistry. 2022;(2):593-604
Abstract
Autophagy is the process of recycling and utilization of degraded organelles and macromolecules in the cell compartments formed during the fusion of autophagosomes with lysosomes. During autophagy induction the healthy and tumor cells adapt themselves to harsh conditions such as cellular stress or insufficient supply of nutrients in the cell environment to maintain their homeostasis. Autophagy is currently seen as a form of programmed cell death along with apoptosis and necroptosis. In recent years multiple studies have considered the autophagy as a potential mechanism of anticancer therapy in malignant glioma. Although, subsequent steps in autophagy development are known and well-described, on molecular level the mechanism of autophagosome initiation and maturation using autophagy-related proteins is under investigation. This article reviews current state about the mechanism of autophagy, its molecular pathways and the most recent studies on roles of autophagy-related proteins and their isoforms in glioma progression and its treatment.
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2.
Current Perspectives on the Role of Matrix Metalloproteinases in the Pathogenesis of Basal Cell Carcinoma.
Tampa, M, Georgescu, SR, Mitran, MI, Mitran, CI, Matei, C, Caruntu, A, Scheau, C, Nicolae, I, Matei, A, Caruntu, C, et al
Biomolecules. 2021;(6)
Abstract
Basal cell carcinoma (BCC) is the most common skin malignancy, which rarely metastasizes but has a great ability to infiltrate and invade the surrounding tissues. One of the molecular players involved in the metastatic process are matrix metalloproteinases (MMPs). MMPs are enzymes that can degrade various components of the extracellular matrix. In the skin, the expression of MMPs is increased in response to various stimuli, including ultraviolet (UV) radiation, one of the main factors involved in the development of BCC. By modulating various processes that are linked to tumor growth, such as invasion and angiogenesis, MMPs have been associated with UV-related carcinogenesis. The sources of MMPs are multiple, as they can be released by both neoplastic and tumor microenvironment cells. Inhibiting the action of MMPs could be a useful therapeutic option in BCC management. In this review that reunites the latest advances in this domain, we discuss the role of MMPs in the pathogenesis and evolution of BCC, as molecules involved in tumor aggressiveness and risk of recurrence, in order to offer a fresh and updated perspective on this field.
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3.
Nicotinamide N-Methyltransferase in Acquisition of Stem Cell Properties and Therapy Resistance in Cancer.
Novak Kujundžić, R, Prpić, M, Đaković, N, Dabelić, N, Tomljanović, M, Mojzeš, A, Fröbe, A, Trošelj, KG
International journal of molecular sciences. 2021;(11)
Abstract
The activity of nicotinamide N-methyltransferase (NNMT) is tightly linked to the maintenance of the nicotinamide adenine dinucleotide (NAD+) level. This enzyme catalyzes methylation of nicotinamide (NAM) into methyl nicotinamide (MNAM), which is either excreted or further metabolized to N1-methyl-2-pyridone-5-carboxamide (2-PY) and H2O2. Enzymatic activity of NNMT is important for the prevention of NAM-mediated inhibition of NAD+-consuming enzymes poly-adenosine -diphosphate (ADP), ribose polymerases (PARPs), and sirtuins (SIRTs). Inappropriately high expression and activity of NNMT, commonly present in various types of cancer, has the potential to disrupt NAD+ homeostasis and cellular methylation potential. Largely overlooked, in the context of cancer, is the inhibitory effect of 2-PY on PARP-1 activity, which abrogates NNMT's positive effect on cellular NAD+ flux by stalling liberation of NAM and reducing NAD+ synthesis in the salvage pathway. This review describes, and discusses, the mechanisms by which NNMT promotes NAD+ depletion and epigenetic reprogramming, leading to the development of metabolic plasticity, evasion of a major tumor suppressive process of cellular senescence, and acquisition of stem cell properties. All these phenomena are related to therapy resistance and worse clinical outcomes.
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4.
Na/K-ATPase: Their role in cell adhesion and migration in cancer.
Silva, CID, Gonçalves-de-Albuquerque, CF, Moraes, BPT, Garcia, DG, Burth, P
Biochimie. 2021;:1-8
Abstract
Na/K-ATPase (NKA) is a p-type transmembrane enzyme formed by three different subunits (α, β, and γ gamma). Primarily responsible for transporting sodium and potassium through the cell membrane, it also plays a critical role in intracellular signaling. The activation of diverse intracellular pathways may trigger cell death, survival, or even cell proliferation. Changes in the NKA functions or expression in isoforms subunits impact pathological conditions, such as cancer. The NKA function affects cell adhesion, motility, and migration, which are different in the physiological and pathological states. All enzyme subunits take part in the cell adhesion process, with the β subunit being the most studied. Thus, herein we aim to highlight NKA' central role in cell adhesion, motility, and migration in cancer cells.
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5.
Synthetic Retinoids as Potential Therapeutics in Prostate Cancer-An Update of the Last Decade of Research: A Review.
Hałubiec, P, Łazarczyk, A, Szafrański, O, Bohn, T, Dulińska-Litewka, J
International journal of molecular sciences. 2021;(19)
Abstract
Prostate cancer (PC) is the second most common tumor in males. The search for appropriate therapeutic options against advanced PC has been in process for several decades. Especially after cessation of the effectiveness of hormonal therapy (i.e., emergence of castration-resistant PC), PC management options have become scarce and the prognosis is poor. To overcome this stage of disease, an array of natural and synthetic substances underwent investigation. An interesting and promising class of compounds constitutes the derivatives of natural retinoids. Synthesized on the basis of the structure of retinoic acid, they present unique and remarkable properties that warrant their investigation as antitumor drugs. However, there is no up-to-date compilation that consecutively summarizes the current state of knowledge about synthetic retinoids with regard to PC. Therefore, in this review, we present the results of the experimental studies on synthetic retinoids conducted within the last decade. Our primary aim is to highlight the molecular targets of these compounds and to identify their potential promise in the treatment of PC.
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6.
New promising developments for potential therapeutic applications of high-dose ascorbate as an anticancer drug.
Testa, U, Pelosi, E, Castelli, G
Hematology/oncology and stem cell therapy. 2021;(3):179-191
Abstract
Vitamin C (ascorbate) is an essential dietary requirement, with fundamental redox, anti-oxidant functions at physiologic concentrations. Vitamin C is a cofactor for Fe2+ and 2-oxoglutarate-dependent dioxygenases, englobing large families of enzymes, including also epigenetic regulators of DNA and histone methylation. Importantly, vitamin C is involved in the control of the activity of TET (ten-eleven translocation) enzymes, key epigenetic regulators. For this spectrum of activities, often involving pathways deregulated in cancer cells, vitamin C possesses some pharmacologic activities that can be exploited in anticancer therapy. In particular, the capacity of pharmacological doses of vitamin C to target redox imbalance and to rescue deregulated epigenetic program observed in some cancer cells represents a consistent therapeutic potentiality. Several recent studies have identified some cancer subsets that could benefit from the pharmacological activities of vitamin C. The identification of these potentially responsive patients will help to carefully define controlled clinical trials aiming to evaluate the anticancer activity of Vitamin C.
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7.
Glucose, Fructose, and Urate Transporters in the Choroid Plexus Epithelium.
Chiba, Y, Murakami, R, Matsumoto, K, Wakamatsu, K, Nonaka, W, Uemura, N, Yanase, K, Kamada, M, Ueno, M
International journal of molecular sciences. 2020;(19)
Abstract
The choroid plexus plays a central role in the regulation of the microenvironment of the central nervous system by secreting the majority of the cerebrospinal fluid and controlling its composition, despite that it only represents approximately 1% of the total brain weight. In addition to a variety of transporter and channel proteins for solutes and water, the choroid plexus epithelial cells are equipped with glucose, fructose, and urate transporters that are used as energy sources or antioxidative neuroprotective substrates. This review focuses on the recent advances in the understanding of the transporters of the SLC2A and SLC5A families (GLUT1, SGLT2, GLUT5, GLUT8, and GLUT9), as well as on the urate-transporting URAT1 and BCRP/ABCG2, which are expressed in choroid plexus epithelial cells. The glucose, fructose, and urate transporters repertoire in the choroid plexus epithelium share similar features with the renal proximal tubular epithelium, although some of these transporters exhibit inversely polarized submembrane localization. Since choroid plexus epithelial cells have high energy demands for proper functioning, a decline in the expression and function of these transporters can contribute to the process of age-associated brain impairment and pathophysiology of neurodegenerative diseases.
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8.
Microenvironment Remodeling and Subsequent Clinical Implications in Diffuse Large B-Cell Histologic Variant of Richter Syndrome.
Augé, H, Notarantonio, AB, Morizot, R, Quinquenel, A, Fornecker, LM, Hergalant, S, Feugier, P, Broséus, J
Frontiers in immunology. 2020;:594841
Abstract
INTRODUCTION Richter Syndrome (RS) is defined as the development of an aggressive lymphoma in the context of Chronic Lymphocytic Leukemia (CLL), with a Diffuse Large B-Cell Lymphoma (DLBCL) histology in 95% cases. RS genomic landscape shares only a few features with de novo DLBCLs and is marked by a wide spectrum of cytogenetic abnormalities. Little is known about RS microenvironment. Therapeutic options and efficacy are limited, leading to a 12 months median overall survival. The new targeted treatments usually effective in CLL fail to obtain long-term remissions in RS. METHODS We reviewed available PubMed literature about RS genomics, PD-1/PD-L1 (Programmed Death 1/Programmed Death Ligand 1) pathway triggering and subsequent new therapeutic options. RESULTS Data from about 207 patients from four landmark papers were compiled to build an overview of RS genomic lesions and point mutations. A number of these abnormalities may be involved in tumor microenvironment reshaping. T lymphocyte exhaustion through PD-L1 overexpression by tumor cells and subsequent PD-1/PD-L1 pathway triggering is frequently reported in solid cancers. This immune checkpoint inhibitor is also described in B lymphoid malignancies, particularly CLL: PD-1 expression is reported in a subset of prolymphocytes from the CLL lymph node proliferation centers. However, there is only few data about PD-1/PD-L1 pathway in RS. In RS, PD-1 expression is a hallmark of recently described « Regulatory B-cells », which interact with tumor microenvironment by producing inhibiting cytokines such as TGF-β and IL-10, impairing T lymphocytes anti-tumoral function. Based upon the discovery of high PD-1 expression on tumoral B lymphocyte from RS, immune checkpoint blockade therapies such as anti-PD-1 antibodies have been tested on small RS cohorts and provided heterogeneous but encouraging results. CONCLUSION RS genetic landscape and immune evasion mechanisms are being progressively unraveled. New protocols using targeted treatments such as checkpoint inhibitors as single agents or in combination with immunochemotherapy are currently being evaluated.
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9.
Targeting ADAM10 in Cancer and Autoimmunity.
Smith, TM, Tharakan, A, Martin, RK
Frontiers in immunology. 2020;:499
Abstract
Generating inhibitors for A Disintegrin And Metalloproteinase 10 (ADAM10), a zinc-dependent protease, was heavily invested in by the pharmaceutical industry starting over 20 years ago. There has been much enthusiasm in basic research for these inhibitors, with a multitude of studies generating significant data, yet the clinical trials have not replicated the same results. ADAM10 is ubiquitously expressed and cleaves many important substrates such as Notch, PD-L1, EGFR/HER ligands, ICOS-L, TACI, and the "stress related molecules" MIC-A, MIC-B and ULBPs. This review goes through the most recent pre-clinical data with inhibitors as well as clinical data supporting the use of ADAM10 inhibitor use in cancer and autoimmunity. It additionally addresses how ADAM10 inhibitor therapy can be improved and if inhibitor therapy can be paired with other drug treatments to maximize effectiveness in various disease states. Finally, it examines the ADAM10 substrates that are important to each disease state and if any of these substrates or ADAM10 itself is a potential biomarker for disease.
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10.
Endoplasmic Reticulum Calcium Pumps and Tumor Cell Differentiation.
Papp, B, Launay, S, Gélébart, P, Arbabian, A, Enyedi, A, Brouland, JP, Carosella, ED, Adle-Biassette, H
International journal of molecular sciences. 2020;(9)
Abstract
Endoplasmic reticulum (ER) calcium homeostasis plays an essential role in cellular calcium signaling, intra-ER protein chaperoning and maturation, as well as in the interaction of the ER with other organelles. Calcium is accumulated in the ER by sarco/endoplasmic reticulum calcium ATPases (SERCA enzymes) that generate by active, ATP-dependent transport, a several thousand-fold calcium ion concentration gradient between the cytosol (low nanomolar) and the ER lumen (high micromolar). SERCA enzymes are coded by three genes that by alternative splicing give rise to several isoforms, which can display isoform-specific calcium transport characteristics. SERCA expression levels and isoenzyme composition vary according to cell type, and this constitutes a mechanism whereby ER calcium homeostasis is adapted to the signaling and metabolic needs of the cell, depending on its phenotype, its state of activation and differentiation. As reviewed here, in several normal epithelial cell types including bronchial, mammary, gastric, colonic and choroid plexus epithelium, as well as in mature cells of hematopoietic origin such as pumps are simultaneously expressed, whereas in corresponding tumors and leukemias SERCA3 expression is selectively down-regulated. SERCA3 expression is restored during the pharmacologically induced differentiation of various cancer and leukemia cell types. SERCA3 is a useful marker for the study of cell differentiation, and the loss of SERCA3 expression constitutes a previously unrecognized example of the remodeling of calcium homeostasis in tumors.