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Journal of Enzyme Inhibition and... Dec 2023Phosphoinositide 3-kinases (PI3K) and phosphoinositide 3-kinase-related protein kinases (PIKK) are two structurally related families of kinases that play vital roles in... (Review)
Review
Phosphoinositide 3-kinases (PI3K) and phosphoinositide 3-kinase-related protein kinases (PIKK) are two structurally related families of kinases that play vital roles in cell growth and DNA damage repair. Dysfunction of PIKK members and aberrant stimulation of the PI3K/AKT/mTOR signalling pathway are linked to a plethora of diseases including cancer. In recent decades, numerous inhibitors related to the PI3K/AKT/mTOR signalling have made great strides in cancer treatment, like copanlisib and sirolimus. Notably, most of the PIKK inhibitors (such as VX-970 and M3814) related to DNA damage response have also shown good efficacy in clinical trials. However, these drugs still require a suitable combination therapy to overcome drug resistance or improve antitumor activity. Based on the aforementioned facts, we summarised the efficacy of PIKK, PI3K, and AKT inhibitors in the therapy of human malignancies and the resistance mechanisms of targeted therapy, in order to provide deeper insights into cancer treatment.
Topics: Humans; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Phosphoinositide-3 Kinase Inhibitors; TOR Serine-Threonine Kinases; Neoplasms; Protein Kinase Inhibitors
PubMed: 37489050
DOI: 10.1080/14756366.2023.2237209 -
Biochimica Et Biophysica Acta.... Oct 2023Macroautophagy is a health-modifying process of engulfing misfolded or aggregated proteins or damaged organelles, coating these proteins or organelles into vesicles,... (Review)
Review
Macroautophagy is a health-modifying process of engulfing misfolded or aggregated proteins or damaged organelles, coating these proteins or organelles into vesicles, fusion of vesicles with lysosomes to form autophagic lysosomes, and degradation of the encapsulated contents. It is also a self-rescue strategy in response to harsh environments and plays an essential role in cancer cells. AMP-activated protein kinase (AMPK) is the central pathway that regulates autophagy initiation and autophagosome formation by phosphorylating targets such as mTORC1 and unc-51 like activating kinase 1 (ULK1). AMPK is an evolutionarily conserved serine/threonine protein kinase that acts as an energy sensor in cells and regulates various metabolic processes, including those involved in cancer. The regulatory network of AMPK is complicated and can be regulated by multiple upstream factors, such as LKB1, AKT, PPAR, SIRT1, or noncoding RNAs. Currently, AMPK is being investigated as a novel target for anticancer therapies based on its role in macroautophagy regulation. Herein, we review the effects of AMPK-dependent autophagy on tumor cell survival and treatment strategies targeting AMPK.
Topics: AMP-Activated Protein Kinases; Protein Serine-Threonine Kinases; Autophagy; Mechanistic Target of Rapamycin Complex 1; Neoplasms
PubMed: 37463638
DOI: 10.1016/j.bbamcr.2023.119537 -
Military Medical Research Dec 2023Cell metabolism plays a pivotal role in tumor progression, and targeting cancer metabolism might effectively kill cancer cells. We aimed to investigate the role of...
BACKGROUND
Cell metabolism plays a pivotal role in tumor progression, and targeting cancer metabolism might effectively kill cancer cells. We aimed to investigate the role of hexokinases in prostate cancer (PCa) and identify a crucial target for PCa treatment.
METHODS
The Cancer Genome Atlas (TCGA) database, online tools and clinical samples were used to assess the expression and prognostic role of ADP-dependent glucokinase (ADPGK) in PCa. The effect of ADPGK expression on PCa cell malignant phenotypes was validated in vitro and in vivo. Quantitative proteomics, metabolomics, and extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) tests were performed to evaluate the impact of ADPGK on PCa metabolism. The underlying mechanisms were explored through ADPGK overexpression and knockdown, co-immunoprecipitation (Co-IP), ECAR analysis and cell counting kit-8 (CCK-8) assays.
RESULTS
ADPGK was the only glucokinase that was both upregulated and predicted worse overall survival (OS) in prostate adenocarcinoma (PRAD). Clinical sample analysis demonstrated that ADPGK was markedly upregulated in PCa tissues vs. non-PCa tissues. High ADPGK expression indicates worse survival outcomes, and ADPGK serves as an independent factor of biochemical recurrence. In vitro and in vivo experiments showed that ADPGK overexpression promoted PCa cell proliferation and migration, and ADPGK inhibition suppressed malignant phenotypes. Metabolomics, proteomics, and ECAR and OCR tests revealed that ADPGK significantly accelerated glycolysis in PCa. Mechanistically, ADPGK binds aldolase C (ALDOC) to promote glycolysis via AMP-activated protein kinase (AMPK) phosphorylation. ALDOC was positively correlated with ADPGK, and high ALDOC expression was associated with worse survival outcomes in PCa.
CONCLUSIONS
In summary, ADPGK is a driving factor in PCa progression, and its high expression contributes to a poor prognosis in PCa patients. ADPGK accelerates PCa glycolysis and progression by activating ALDOC-AMPK signaling, suggesting that ADPGK might be an effective target and marker for PCa treatment and prognosis evaluation.
Topics: Humans; Male; Glucokinase; Prostate; AMP-Activated Protein Kinases; Prostatic Neoplasms
PubMed: 38082365
DOI: 10.1186/s40779-023-00500-9 -
Cellular and Molecular Life Sciences :... Sep 2023The receptor interacting protein kinases (RIPK) are a family of serine/threonine kinases that are involved in the integration of various stress signals. In response to... (Review)
Review
The receptor interacting protein kinases (RIPK) are a family of serine/threonine kinases that are involved in the integration of various stress signals. In response to several extracellular and/or intracellular stimuli, RIP kinases engage signaling cascades leading to the activation of NF-κB and mitogen-activated protein kinases, cell death, inflammation, differentiation and Wnt signaling and can have kinase-dependent and kinase-independent functions. Although it was previously suggested that seven RIPKs are part of the RIPK family, phylogenetic analysis indicates that there are only five genuine RIPKs. RIPK1 and RIPK3 are mainly involved in controlling and executing necroptosis in keratinocytes, while RIPK4 controls proliferation and differentiation of keratinocytes and thereby can act as a tumor suppressor in skin. Therefore, in this review we summarize and discuss the functions of RIPKs in skin homeostasis as well as the signaling pathways involved.
Topics: Phylogeny; Skin; Keratinocytes; Mitogen-Activated Protein Kinases; Protein Serine-Threonine Kinases
PubMed: 37688617
DOI: 10.1007/s00018-023-04917-2 -
Oncogene Nov 2023Most of our understanding regarding the involvement of SRC-family tyrosine kinases in cancer has stemmed from studies focused on the prototypical SRC oncogene. However,... (Review)
Review
Most of our understanding regarding the involvement of SRC-family tyrosine kinases in cancer has stemmed from studies focused on the prototypical SRC oncogene. However, emerging research has shed light on the important role of YES signaling in oncogenic transformation, tumor growth, metastatic progression, and resistance to various cancer therapies. Clinical evidence indicates that dysregulated expression or activity of YES is a frequent occurrence in human cancers and is associated with unfavorable outcomes. These findings provide a compelling rationale for specifically targeting YES in certain cancer subtypes. Here, we review the crucial role of YES in cancer and discuss the challenges associated with translating preclinical observations into effective YES-targeted therapies.
Topics: Humans; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-yes; Protein-Tyrosine Kinases; src-Family Kinases; Neoplasms
PubMed: 37848624
DOI: 10.1038/s41388-023-02860-x -
Biochemical Pharmacology Sep 2023Alcohol use is a major risk factor for death and disability, resulting in a significant global disease burden. Alcoholic steatohepatitis (ASH) reflects an acute...
BACKGROUND
Alcohol use is a major risk factor for death and disability, resulting in a significant global disease burden. Alcoholic steatohepatitis (ASH) reflects an acute exacerbation of alcoholic liver disease (ALD) and is a growing health care and economic burden worldwide. Pyroptosis plays a central role in the pathogenesis of ASH. Nt5e (CD73) is a cell surface ecto-5'-nucleotidase, which is a key enzyme that converts the proinflammatory signal ATP to the anti-inflammatory mediator adenosine (ADO). Studies have found that CD73 is involved in multiple diseases and can alleviate gasdermin D (GSDMD)-mediated pyroptosis; however, its role and mechanism in ASH are not explicit.
AIM
To investigate the role and mechanisms of CD73-mediated hepatocyte pyroptosis in alcohol-induced liver injury through in vivo and in vitro experiments.
METHODS
CD73 knockout (CD73) mice, wild-type (WT) mice, and AML-12 cells were used to evaluate the effect of CD73 on hepatocyte pyroptosis in vivo and in vitro. A combination of molecular and histological methods was performed to assess pyroptosis and investigate the mechanism both in vivo and in vitro.
RESULTS
The protein expression of CD73 and pyroptosis pathway-associated genes was increased significantly in hepatocyte injury model both in vivo and in vitro. In vivo, CD73 knockout dramatically aggravated inflammatory damage, lipid accumulation, and hepatocyte pyroptosis in the liver. In vitro, overexpression of CD73 by pEGFP-C1/CD73 can decrease NLRP3 inflammasome activation and pyroptosis in hepatocytes. Further analysis revealed that the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is a possible mechanism of CD73 regulation. Meanwhile, this pathological process was inhibited after the use of PI3K inhibitors.
CONCLUSION
Our results show a novel function of CD73 regulates hepatocytes pyroptosis and highlights the therapeutic opportunity for reducing the disease process in ALD.
Topics: Animals; Mice; Fatty Liver, Alcoholic; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Phosphatidylinositol 3-Kinase; 5'-Nucleotidase; Pyroptosis; Hepatocytes; Liver Diseases, Alcoholic
PubMed: 37611643
DOI: 10.1016/j.bcp.2023.115753 -
Nature Communications Sep 2023Nonalcoholic steatohepatitis (NASH) is triggered by hepatocyte death through activation of caspase 6, as a result of decreased adenosine monophosphate (AMP)-activated...
Nonalcoholic steatohepatitis (NASH) is triggered by hepatocyte death through activation of caspase 6, as a result of decreased adenosine monophosphate (AMP)-activated protein kinase-alpha (AMPKα) activity. Increased hepatocellular death promotes inflammation which drives hepatic fibrosis. We show that the nuclear-localized mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP1) is upregulated in NASH patients and in NASH diet fed male mice. The focus of this work is to investigate whether and how MKP1 is involved in the development of NASH. Under NASH conditions increased oxidative stress, induces MKP1 expression leading to nuclear p38 MAPK dephosphorylation and decreases liver kinase B1 (LKB1) phosphorylation at a site required to promote LKB1 nuclear exit. Hepatic deletion of MKP1 in NASH diet fed male mice releases nuclear LKB1 into the cytoplasm to activate AMPKα and prevents hepatocellular death, inflammation and NASH. Hence, nuclear-localized MKP1-p38 MAPK-LKB1 signaling is required to suppress AMPKα which triggers hepatocyte death and the development of NASH.
Topics: Animals; Male; Mice; AMP-Activated Protein Kinases; Inflammation; Mitogen-Activated Protein Kinase 14; Non-alcoholic Fatty Liver Disease; Phosphorylation; Protein Serine-Threonine Kinases
PubMed: 37669951
DOI: 10.1038/s41467-023-41145-5 -
Journal of Cancer Research and Clinical... Aug 2023Tyrosine kinase Fyn is a member of the Src family of kinases. In addition to the wild type, three mRNA splice isoforms of Fyn have been identified; Fyn-B, Fyn-T, and... (Review)
Review
BACKGROUND
Tyrosine kinase Fyn is a member of the Src family of kinases. In addition to the wild type, three mRNA splice isoforms of Fyn have been identified; Fyn-B, Fyn-T, and Fyn-C. Fyn-T is highly expressed in T lymphocytes, and its expression level is significantly higher in mature T cells than in immature T cells. The abnormal expression of Fyn is closely related to the metabolism, proliferation, and migration of tumor cells. Recent studies have shown that Fyn is expressed in a variety of tumor tissues, and its expression and function vary among different tumors. In some tumors, Fyn acts as a pro-oncogene to promote tumor proliferation and metastasis. Moreover, Fyn mutations have been detected in many hematological tumors in recent years, suggesting a critical regulatory role of Fyn in the development of malignancies.
METHODS
This review analyzed the relevant literature in PubMed and other databases.
PURPOSE
The aim of this study was to systemically review recent research findings on various aspects of Fyn in the pathogenesis and treatment of different types of hematological malignancies and suggests possible future research directions for targeted tumor therapy.
CONCLUSION
Fyn could be a novel prognostic marker and therapeutic target. Treatment option targeting Fyn might be beneficial for future studies.
Topics: Humans; Hematologic Neoplasms; Neoplasms; Phosphotransferases; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-fyn; src-Family Kinases
PubMed: 36754870
DOI: 10.1007/s00432-023-04608-2 -
International Journal of Molecular... Oct 2023Necroptosis, which is distinct from apoptosis and necrosis, serves a crucial role in ontogeny and the maintenance of homeostasis. In the last decade, it has been... (Review)
Review
Necroptosis, which is distinct from apoptosis and necrosis, serves a crucial role in ontogeny and the maintenance of homeostasis. In the last decade, it has been demonstrated that the pathogenesis of cardiovascular diseases is also linked to necroptosis. Receptor interaction protein kinase (RIPK) 1, RIPK3 and mixed lineage kinase domain‑like protein serve vital roles in necroptosis. In addition to the aforementioned necroptosis‑related components, calcium/calmodulin‑dependent protein kinase II (CaMKII) has been identified as a novel substrate for RIPK3 that promotes the opening of the mitochondrial permeability transition pore (mPTP), and thus, mediates necroptosis of myocardial cells through the RIPK3‑CaMKII‑mPTP signaling pathway. The present review provides an overview of the current knowledge of the RIPK3‑CaMKII‑mPTP‑mediated necroptosis signaling pathway in cardiovascular diseases, focusing on the role of the RIPK3‑CaMKII‑mPTP signaling pathway in acute myocardial infarction, ischemia‑reperfusion injury, heart failure, abdominal aortic aneurysm, atherosclerosis, diabetic cardiomyopathy, hypertrophic cardiomyopathy, atrial fibrillation, and the cardiotoxicity associated with antitumor drugs and other chemicals. Finally, the present review discusses the research status of drugs targeting the RIPK3‑CaMKII‑mPTP signaling pathway.
Topics: Humans; Cardiovascular Diseases; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Necroptosis; Heart Failure; Signal Transduction; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 37654208
DOI: 10.3892/ijmm.2023.5301 -
Journal of Ovarian Research Jul 2023High-grade serous ovarian cancers (HGSCs) display a high degree of complex genetic alterations. In this study, we identified germline and somatic genetic alterations in...
BACKGROUND
High-grade serous ovarian cancers (HGSCs) display a high degree of complex genetic alterations. In this study, we identified germline and somatic genetic alterations in HGSC and their association with relapse-free and overall survival. Using a targeted capture of 557 genes involved in DNA damage response and PI3K/AKT/mTOR pathways, we conducted next-generation sequencing of DNA from matched blood and tumor tissue from 71 HGSC participants. In addition, we performed the OncoScan assay on tumor DNA from 61 participants to examine somatic copy number alterations (SCNA).
RESULTS
Approximately one-third of tumors had loss-of-function (LOF) germline (18/71, 25.4%) or somatic (7/71, 9.9%) variants in the DNA homologous recombination repair pathway genes BRCA1, BRCA2, CHEK2, MRE11A, BLM, and PALB2. LOF germline variants also were identified in other Fanconi anemia genes and in MAPK and PI3K/AKT/mTOR pathway genes. Most tumors harbored somatic TP53 variants (65/71, 91.5%). Using the OncoScan assay on tumor DNA from 61 participants, we identified focal homozygous deletions in BRCA1, BRCA2, MAP2K4, PTEN, RB1, SLX4, STK11, CREBBP, and NF1. In total, 38% (27/71) of HGSC patients harbored pathogenic variants in DNA homologous recombination repair genes. For patients with multiple tissues from the primary debulking or from multiple surgeries, the somatic mutations were maintained with few newly acquired point mutations suggesting that tumor evolution was not through somatic mutations. There was a significant association of LOF variants in homologous recombination repair pathway genes and high-amplitude somatic copy number alterations. Using GISTIC analysis, we identified NOTCH3, ZNF536, and PIK3R2 in these regions that were significantly associated with an increase in cancer recurrence and a reduction in overall survival.
CONCLUSIONS
From 71 patients with HGCS, we performed targeted germline and tumor sequencing and provided a comprehensive analysis of these 557 genes. We identified germline and somatic genetic alterations including somatic copy number alterations and analyzed their associations with relapse-free and overall survival. This single-site long-term follow-up study provides additional information on genetic alterations related to occurrence and outcome of HGSC. Our findings suggest that targeted treatments based on both variant and SCNA profile potentially could improve relapse-free and overall survival.
Topics: Humans; Female; Ovarian Neoplasms; Follow-Up Studies; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Neoplasm Recurrence, Local; Genomics; TOR Serine-Threonine Kinases
PubMed: 37460928
DOI: 10.1186/s13048-023-01234-x