1,721,057 research outputs found
Molecular events in acute myeloid leukemogenesis: a model from core binding factor leukemia
No full textFZD4 (frizzled class receptor 4)
No full textFzd4 is a receptor for Wnt proteins, belonging to the frizzled receptors family. Its stimulation can activate both Wnt/β-catenin canonical and Wnt/Ca2+ non canonical pathways. This receptor plays an important role in the development processes, in particular in the retinal vascularization: it binds the Norrin ligand, a Wnt-unrelated growth factor, and activates β-catenin signalling pathway. Mutations of FZD4 gene are associated with Familial Exudative Vitreoretinopathy (FEVR). Recently dysregulation of FZD4 expression has been reported in different type of cancers, but FZD4 contribution in tumor pathogenesis and progression is still not entirely elucidated
Carbonic Anhydrase 9: mastering ferropoptosis resistance in cancer, protector or weak point?
Full text linkFerroptosis is a recently discovered form of iron-dependent programmed cell death, characterized by the toxic accumulation of lipid peroxides that disrupt cell membrane function. Cancer cells are particularly susceptible to ferroptosis due to their high iron requirements for growth and a metabolism that creates an intracellular environment conducive to triggering this death mechanism. However, cancer cells counteract this vulnerability through carbonic anhydrase 9 (CA9), a protein that regulates intracellular pH, ensuring conditions unfavorable for ferroptosis.\\nThis minireview explores the factors necessary to induce ferroptosis and examines how CA9 not only protects cancer cells but also facilitates their migration. The aim is to highlight potential therapeutic opportunities arising from disrupting the functionality of this protein
Beyond the Warburg Effect: KRAS/MAPK-Driven Uridine Utilization in Glucose-Deprived Pancreatic Ductal Adenocarcinoma
Full text linkCancer cells exhibit a significantly altered metabolic phenotype, characterized by a distinctive reliance on glucose to support their growth, survival, and proliferation through a unique energy extraction mechanism. This metabolic reprogramming is epitomized by an increased glucose demand and a preference for lactic fermentation, even in the presence of oxygen, rather than the conventional citric acid cycle utilized by non-cancerous cells. This phenomenon, known as the Warburg Effect, serves as a hallmark of cancer metabolism. The implications of this metabolic shift extend beyond cellular energy dynamics, as it initiates the development of a novel tumor microenvironment characterized by adverse conditions such as hypoxia and glucose scarcity, particularly pronounced in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDA), a notably therapy-resistant malignancy, exemplifies this metabolic adaptation. Under conditions of glucose limitation, PDA cells demonstrate a remarkable ability to utilize uridine as a primary energy substrate, a process regulated by uridine phosphorylase 1 (UPP1). UPP1 plays a central role in metabolizing uridine-derived ribose, thereby supporting central carbon metabolism, maintaining redox homeostasis, and promoting cell survival and proliferation under nutrient-restricted conditions. This metabolic pathway is under the regulatory control of KRAS–MAPK signaling, which is further amplified in response to nutrient deprivation. Consistent with these observations, tumor specimens show elevated UPP1 expression compared to normal tissues, correlating with poor clinical outcomes. The availability of uridine in the tumor microenvironment and its active catabolism within tumor cells underscore the clinical importance of these metabolic processes. Notably, genetic ablation of UPP1 disrupts uridine utilization and significantly suppresses PDA growth in murine models.
In summary, this review highlights uridine metabolism as a pivotal compensatory mechanism enabling PDA cells to adapt to nutrient-deprived environments. By influencing the Warburg Effect, uridine utilization integrates nucleotide metabolism with energy production, revealing critical molecular pathways that regulate glucose metabolism in tumor cells. These findings provide novel insights into the metabolic flexibility of PDA and identify potential therapeutic targets for its treatment
CSNK2A2 (casein kinase 2 alpha 2)
No full textCSNK2A2 gene, 16q21, has a role in regulating the phosphorylation and circulation of old proteasomes by encoding the catalytic α' subunit of casein kinase 2 (CK2α'). Casein kinase 2 is a serine/threonine protein kinase that phosphorylates acidic proteins. It can regulate Wnt signalling by phosphorylating CTNNB1 and the transcription factor LEF1 and for this reason, it is involved in some cellular key processes such as cell cycle progression, inhibition of apoptosis, DNA damage repair, differentiation and transcription but also viral infection. CSNK2A2 is a cancer-related gene and its upregulation has been detected is many cancers such as glioblastoma multiforme, colorectal cancer, breast cancer and ovarian cancer, and also in some diseases such as diabetes, theileriasis in cattle and distal muscular dystrophy with anterior tibial onset in mice are associated with CSNK2A2
The Kasumi-1 cell line : a t(8;21)-kit mutant model for acute myeloid leukemia
No full textThe Kasumi-1 cell line is an intensively investigated model system of Acute Myeloid Leukemia with t(8;21) translocation, that represents 1 of the 2 main subtypes of Core Binding Factor Leukemia (CBFL). Since establishment in 1991 the Kasumi-1 cell line has provided the tool to study the peculiar molecular, morphologic, immunophenotypic findings of AML with t(8;21) and the functional consequences of the AML1-ETO fusion oncogene on myeloid differentiation. Leukemogenesis involves multiple genetic changes and, as suggested by murine experiments and other findings in humans, AML1-ETO expression may not be sufficient for full blown leukemia. In agreement with the "two hits" model of leukemogenesis, based on the cooperation between 1 class of mutations that impair hematopoietic differentiation and a second class of mutations that confer a proliferative and/or survival advantage to hematopoietic progenitors an activating mutation in the tyrosine kinase domain of the c-kit gene was identified in the AML1/ETO expressing Kasumi-1 cell line. The dosage of the Asn822Lys mutated allele was shown to be about 5-fold compared to the normal allele and c-kit amplification was found to map to minute 4cen-q11 marker chromosomes, likely derived from the extra chromosome 4 recorded in the newly established cell line. The combination of t(8;21) and trisomy 4 leading to enhanced dosage of a mutated kit allele is a feature of a few CBFL patients reproduced by the Kasumi-1 cell model. The Kasumi-1 cell line, paralleling the commitment stage of CBF leukemia also provides a valuable resource to investigate the effect of tyrosine kinase kit mutant on the main KIT-regulated signal transduction pathways, i.e. MAPK, PI3K/AKT and STAT3 and the diverse inhibitory effect exerted by STI 571 on these KIT mutant activated pathways. PI3K-dependent activation of AKT and STAT activation was observed in Kasumi-1 cells. Contrary to the expectations for an amplified tyrosine kinase kit mutant, we found that STI 571 inhibited KIT Asn822Lys tyrosine phosphorylation and downstream JNK and STAT3 effectors in Kasumi-1 cells, but had no effect on constitutive activation of AKT, suggesting that signaling by tyrosine kinases other than KIT may be responsible for its activation in Kasumi-1 cells. Independent findings on the same model system provide complementary insights into designing strategies for treatment of CBF leukemia associated with mutations in the KIT catalytic domain
PTPN13 (Protein tyrosine phosphatase, non-receptor type 13)
Full text linkReview on PTPN13 (Protein tyrosine phosphatase, non-receptor type 13), with data on DNA, on the protein encoded, and where the gene is implicated
Prognostic markers in AML : focus on CBFL
No full textAcute myeloid leukemia (AML) is a heterogeneous disease increasing in frequency owing to an aging population. Decisions on intensive induction treatments, intensification and allografting rely on the ability to divide an apparently homogeneous group according to risk. A wide range of clinical, cytogenetic and molecular variables may be used to inform this task; here we examine those variables useful in assessing prognosis for a patient with non-acute promyelocitic AML focusing on core binding factor leukemia. In clinical practice, when counseling an individual patient with AML, a range of well-known clinical variables (age, performance status and tumor burden) and genetic variables (cytogenetic and gene mutation) must be considered to better define the prognostic risk
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