scholarly journals Therapeutic Implications of Targeting AKT Signaling in Melanoma

2011 ◽  
Vol 2011 ◽  
pp. 1-20 ◽  
Author(s):  
SubbaRao V. Madhunapantula ◽  
Gavin P. Robertson
Keyword(s):  
Pi3k Pathway ◽  
Term Treatment ◽  
Negative Regulator ◽  
Phosphatase And Tensin Homolog ◽  
Key Enzymes ◽  
Therapeutic Implications ◽  
Cellular Processes ◽  
Tensin Homolog ◽  
Stage Disease ◽  
Long Term Treatment

Identification of key enzymes regulating melanoma progression and drug resistance has the potential to lead to the development of novel, more effective targeted agents for inhibiting this deadly form of skin cancer. The Akt3, also known as protein kinase B gamma, pathway enzymes regulate diverse cellular processes including proliferation, survival, and invasion thereby promoting the development of melanoma. Accumulating preclinical evidence demonstrates that therapeutic agents targeting these kinases alone or in combination with other pathway members could be effective for the long-term treatment of advanced-stage disease. However, currently, no selective and effective therapeutic agent targeting these kinases has been identified for clinical use. This paper provides an overview of the key enzymes of the PI3K pathway with emphasis placed on Akt3 and the negative regulator of this kinase called PTEN (phosphatase and tensin homolog deleted on chromosome 10). Mechanisms regulating these enzymes, their substrates and therapeutic implications of targeting these proteins to treat melanoma are also discussed. Finally, key issues that remain to be answered and future directions for interested researchers pertaining to this signaling cascade are highlighted.

scholarly journals PINK1/Parkin Mediated Mitophagy, Ca2+ Signalling, and ER–Mitochondria Contacts in Parkinson’s Disease

2020 ◽  
Vol 21 (5) ◽  
pp. 1772 ◽  
Author(s):  
Lucia Barazzuol ◽  
Flavia Giamogante ◽  
Marisa Brini ◽  
Tito Calì
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Endoplasmic Reticulum ◽  
Neurodegenerative Diseases ◽  
Current Knowledge ◽  
Phosphatase And Tensin Homolog ◽  
Cellular Processes ◽  
Selective Degradation ◽  
Contact Sites ◽  
Tensin Homolog

Endoplasmic reticulum (ER)–mitochondria contact sites are critical structures for cellular function. They are implicated in a plethora of cellular processes, including Ca2+ signalling and mitophagy, the selective degradation of damaged mitochondria. Phosphatase and tensin homolog (PTEN)-induced kinase (PINK) and Parkin proteins, whose mutations are associated with familial forms of Parkinson’s disease, are two of the best characterized mitophagy players. They accumulate at ER–mitochondria contact sites and modulate organelles crosstalk. Alterations in ER–mitochondria tethering are a common hallmark of many neurodegenerative diseases including Parkinson’s disease. Here, we summarize the current knowledge on the involvement of PINK1 and Parkin at the ER–mitochondria contact sites and their role in the modulation of Ca2+ signalling and mitophagy.

scholarly journals Modeling PTEN overexpression-induced microcephaly in human brain organoids

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Navroop Dhaliwal ◽  
Wendy W.Y. Choi ◽  
Julien Muffat ◽  
Yun Li
Keyword(s):  
Human Brain ◽  
Human Genetics ◽  
Negative Regulator ◽  
Akt Inhibitor ◽  
Chromosome 10 ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Pi3k Signaling Pathway ◽  
Brain Organoid ◽  
Phosphoinositide 3 Kinase

AbstractThe phosphatase and tensin homolog (PTEN) protein, encoded by the PTEN gene on chromosome 10, is a negative regulator of the phosphoinositide 3-kinase (PI3K) signaling pathway. Loss of PTEN has been linked to an array of human diseases, including neurodevelopmental disorders such as macrocephaly and autism. However, it remains unknown whether increased dosage of PTEN can lead to human disease. A recent human genetics study identifies chromosome 10 microduplication encompassing PTEN in patients with microcephaly. Here we generated a human brain organoid model of increased PTEN dosage. We showed that mild PTEN overexpression led to reduced neural precursor proliferation, premature neuronal differentiation, and the formation of significantly smaller brain organoids. PTEN overexpression resulted in decreased AKT activation, and treatment of wild-type organoids with an AKT inhibitor recapitulated the reduced brain organoid growth phenotypes. Together, our findings provide functional evidence that PTEN is a dosage-sensitive gene that regulates human neurodevelopment, and that increased PTEN dosage in brain organoids results in microcephaly-like phenotypes.

scholarly journals Peroxiredoxin III Protects Tumor Suppressor PTEN from Oxidation by 15-Hydroperoxy-eicosatetraenoic Acid

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Ying Zhang ◽  
Jiyoung Park ◽  
Seong-Jeong Han ◽  
Yongwoon Lim ◽  
Iha Park ◽  
...  
Keyword(s):  
Redox Regulation ◽  
Lipid Peroxide ◽  
Lipid Peroxides ◽  
Mouse Embryonic Fibroblast ◽  
Cysteine Residue ◽  
Eicosatetraenoic Acid ◽  
Phosphatase And Tensin Homolog ◽  
Active Site Cysteine ◽  
Cellular Processes ◽  
Tensin Homolog

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a lipid and protein phosphatase that coordinates various cellular processes. Its activity is regulated by the reversible oxidation of an active-site cysteine residue by H2O2 and thioredoxin. However, the potential role of lipid peroxides in the redox regulation of PTEN remains obscure. To evaluate this, 15-hydroperoxy-eicosatetraenoic acid (15s-HpETE), a lipid peroxide, was employed to investigate its effect on PTEN using molecular and cellular-based assays. Exposure to 15s-HpETE resulted in the oxidation of recombinant PTEN. Reversible oxidation of PTEN was also observed in mouse embryonic fibroblast (MEF) cells treated with a 15s-HpETE and Lipofectamine mixture. The oxidative dimerization of thioredoxin was found simultaneously. In addition, the absence of peroxiredoxin III aggravated 15s-HpETE-induced PTEN oxidation in MEF cells. Our study provides novel insight into the mechanism linking lipid peroxidation to the etiology of tumorigenesis.

scholarly journals Revising PTEN in the Era of Immunotherapy: New Perspectives for an Old Story

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1525 ◽  
Author(s):  
Geny Piro ◽  
Carmine Carbone ◽  
Luisa Carbognin ◽  
Sara Pilotto ◽  
Chiara Ciccarese ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Current Knowledge ◽  
Phosphatase And Tensin Homolog ◽  
Cancer Immunoediting ◽  
Multiple Tumor ◽  
Cellular Processes ◽  
Tensin Homolog ◽  
Future Clinical Practice ◽  
Cancer Intervention

Immunotherapy has emerged as the new therapeutic frontier of cancer treatment, showing enormous survival benefits in multiple tumor diseases. Although undeniable success has been observed in clinical trials, not all patients respond to treatment. Different concurrent conditions can attenuate or completely abrogate the usefulness of immunotherapy due to the activation of several escape mechanisms. Indeed, the tumor microenvironment has an almost full immunosuppressive profile, creating an obstacle to therapeutic treatment. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) governs a plethora of cellular processes, including maintenance of genomic stability, cell survival/apoptosis, migration, and metabolism. The repertoire of PTEN functions has recently been expanded to include regulation of the tumor microenvironment and immune system, leading to a drastic reevaluation of the canonical paradigm of PTEN action with new potential implications for immunotherapy-based approaches. Understanding the implication of PTEN in cancer immunoediting and immune evasion is crucial to develop new cancer intervention strategies. Recent evidence has shown a double context-dependent role of PTEN in anticancer immunity. Here we summarize the current knowledge of PTEN’s role at a crossroads between tumor and immune compartments, highlighting the most recent findings that are likely to change future clinical practice.

Hippocampal brain amines in methotrexate-induced learning and memory deficit

2002 ◽  
Vol 80 (11) ◽  
pp. 1076-1084 ◽  
Author(s):  
Sampath Madhyastha ◽  
S N Somayaji ◽  
M S Rao ◽  
K Nalini ◽  
K Laxminarayana Bairy
Keyword(s):  
Learning And Memory ◽  
Cognitive Dysfunction ◽  
Conditioned Avoidance ◽  
Term Treatment ◽  
Cresyl Violet ◽  
Intrathecal Methotrexate ◽  
Avoidance Task ◽  
Therapeutic Implications ◽  
Brain Amines ◽  
Long Term Treatment

Intrathecal methotrexate in children with leukemia is known to cause seizures, dementia, leukoencephalo pathy, and cognitive dysfunction after long-term treatment. To investigate the cognitive dysfunction, male Wistar rats were given multiple intracerebroventricular injections of methotrexate. Its effect on behaviour was tested in the two-compartment conditioned avoidance task and dark–bright arena test. Levels of brain amines in the hippocampal region of the brain were estimated by HPLC. The qualitative and quantitative histopathological changes in the different regions of the hippocampus were studied by cresyl violet staining. Multiple injections (1 or 2 mg/kg) produced convulsions and learning and memory impairment but did not induce anxiolytic activity. They also reduced concentrations of all three brain amines (norepinephrine, dopamine, and serotonin) and the serotonin metabolite 5-hydroxyindoleacetic acid. The CA4 region of the hippocampus was severely affected by intraventricular methotrexate. Disruption of brain monoamines has been proposed as a cause of brain dysfunction from this chemotherapy, and that disruption may in turn involve cytotoxic effects of methotrexate on brain tissue. The outcomes of this study may have therapeutic implications in the management of cancer conditions, particularly in childhood lymphoblastic leukemia.Key words: methotrexate, hippocampus, norepinephrine, dopamine, serotonin, learning and memory.

scholarly journals Intestinal epithelial-specific PTEN inactivation results in tumor formation

2011 ◽  
Vol 301 (5) ◽  
pp. G856-G864 ◽  
Author(s):  
Do-Sun Byun ◽  
Naseem Ahmed ◽  
Shannon Nasser ◽  
Joongho Shin ◽  
Sheren Al-Obaidi ◽  
...  
Keyword(s):  
Cell Fate ◽  
Intestinal Epithelium ◽  
Suppressor Gene ◽  
Major Effect ◽  
Tumor Formation ◽  
Negative Regulator ◽  
Intestinal Epithelial ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Pten Deletion

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of phosphatidylinositol 3-kinase (PI3K) signaling that is frequently inactivated in colorectal cancer through mutation, loss of heterozygosity, or epigenetic mechanisms. The aim of this study was to determine the effect of intestinal-specific PTEN inactivation on intestinal epithelial homeostasis and tumorigenesis. PTEN was deleted specifically in the intestinal epithelium, by crossing PTEN Lox/ Lox mice with villin Cre mice. PTEN was robustly expressed in the intestinal epithelium and maximally in the differentiated cell compartment. Targeted inactivation of PTEN in the intestinal epithelium of PTEN Lox/ Lox/villin Cre mice was confirmed by genotyping, immunohistochemistry, and qPCR. While intestinal-specific PTEN deletion did not have a major effect on cell fate determination or proliferation in the small intestine, it did increase phosphorylated (p) protein kinase B (AKT) expression in the intestinal epithelium, and 19% of animals developed small intestinal adenomas and adenocarcinomas at 12 mo of age. These tumors demonstrated pAKT and nuclear β-catenin staining, indicating simultaneous activation of the PI3K/AKT and Wnt signaling pathways. These findings demonstrate that, while PTEN inactivation alone has a minimal effect on intestinal homeostasis, it can facilitate tumor promotion upon deregulation of β-catenin/TCF signaling, further establishing PTEN as a bona fide tumor suppressor gene in intestinal cancer.

scholarly journals Targeting mTOR in Glioblastoma: Rationale and Preclinical/Clinical Evidence

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Carmen Mecca ◽  
Ileana Giambanco ◽  
Rosario Donato ◽  
Cataldo Arcuri
Keyword(s):  
Therapeutic Strategy ◽  
Molecular Mechanisms ◽  
Clinical Evidence ◽  
Survival Rates ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatase And Tensin Homolog ◽  
Cellular Processes ◽  
Mechanistic Target Of Rapamycin ◽  
Tensin Homolog ◽  
Different Types

The mechanistic target of rapamycin (mTOR) drives several physiologic and pathologic cellular processes and is frequently deregulated in different types of tumors, including glioblastoma (GBM). Despite recent advancements in understanding the molecular mechanisms involved in GBM biology, the survival rates of this tumor are still disappointing, primarily due to the lack of efficacious treatments. The phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mTOR pathway has emerged as a crucial player in GBM development and progression. However, to date, all the attempts to target this pathway with PI3K, AKT, or mTORC1 inhibitors failed to improve the outcome of patients with GBM. Despite these discouraging results, recent evidence pointed out that the blockade of mTORC2 might provide a useful therapeutic strategy for GBM, with the potential to overcome the limitations that mTORC1 inhibitors have shown so far. In this review, we analyzed the rationale of targeting mTOR in GBM and the available preclinical and clinical evidence supporting the choice of this therapeutic approach, highlighting the different roles of mTORC1 and mTORC2 in GBM biology.

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