Besides many other mutations in known cancer driver genes, mantle cell lymphoma (MCL) is characterized by recurrent genetic alterations of important regulators of the phosphoinositol-3-kinase (PI3K) cascade including PIK3CA gains and PTEN losses. To evaluate the biological and functional consequences of these aberrations in MCL, we have introduced transgenic expression of PIK3CA (PIK3CA UP) and performed knockout/knockdown of PTEN gene (PTEN KO/KD) in 5 MCL cell lines. The modified cell lines were tested for associated phenotypes including dependence on upstream B-cell receptor (BCR) signaling (by an additional BCR knockout). PIK3CA overexpression decreased the dependence of the tested MCL on prosurvival signaling from BCR, decreased levels of oxidative phosphorylation, and increased resistance to 2-deoxy-glucose, a glycolysis inhibitor. Unchanged protein kinase B (AKT) phosphorylation status and unchanged sensitivity to a battery of PI3K inhibitors suggested that PIK3CA gain might affect MCL cells in AKT-independent manner. PTEN KO was associated with a more distinct phenotype: AKT hyperphosphorylation and overactivation, increased resistance to multiple inhibitors (most of the tested PI3K inhibitors, Bruton tyrosine kinase inhibitor ibrutinib, and BCL2 inhibitor venetoclax), increased glycolytic rates with resistance to 2-deoxy-glucose, and significantly decreased dependence on prosurvival BCR signaling. Our results suggest that the frequent aberrations of the PI3K pathway may rewire associated signaling with lower dependence on BCR signaling, better metabolic and hypoxic adaptation, and targeted therapy resistance in MCL.
- MeSH
- chemorezistence genetika MeSH
- cílená molekulární terapie MeSH
- fosfatidylinositol-3-kinasy třídy I * genetika metabolismus MeSH
- fosfatidylinositol-3-kinasy metabolismus MeSH
- fosfohydroláza PTEN * metabolismus genetika MeSH
- lidé MeSH
- lymfom z plášťových buněk * farmakoterapie genetika metabolismus MeSH
- nádorové buněčné linie MeSH
- protoonkogenní proteiny c-akt metabolismus MeSH
- receptory antigenů B-buněk metabolismus MeSH
- signální transdukce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Sarcoma is a heterogeneous group of malignancies often resistant to conventional chemotherapy and radiation therapy. The phosphatidylinositol-3-kinase/ protein kinase B /mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway has emerged as a critical cancer target due to its central role in regulating key cellular processes such as cell growth, proliferation, survival, and metabolism. Dysregulation of this pathway has been implicated in the development and progression of bone sarcomas (BS) and soft tissue sarcomas (STS). PI3K/Akt/mTOR inhibitors have shown promising preclinical and clinical activity in various cancers. These agents can inhibit the activation of PI3K, Akt, and mTOR, thereby reducing the downstream signaling events that promote tumor growth and survival. In addition, PI3K/Akt/mTOR inhibitors have been shown to enhance the efficacy of other anticancer therapies, such as chemotherapy and radiation therapy. The different types of PI3K/Akt/mTOR inhibitors vary in their specificity, potency, and side effect profiles and may be effective depending on the specific sarcoma type and stage. The molecular targeting of PI3K/Akt/mToR pathway using drugs, phytochemicals, nanomaterials (NMs), and microbe-derived molecules as Pan-PI3K inhibitors, selective PI3K inhibitors, and dual PI3K/mTOR inhibitors have been delineated. While there are still challenges to be addressed, the preclinical and clinical evidence suggests that these inhibitors may significantly improve patient outcomes. Further research is needed to understand the potential of these inhibitors as sarcoma therapeutics and to continue developing more selective and effective agents to meet the clinical needs of sarcoma patients.
- MeSH
- antitumorózní látky * farmakologie chemie terapeutické užití MeSH
- fosfatidylinositol-3-kinasy * metabolismus MeSH
- inhibitory fosfoinositid-3-kinasy farmakologie terapeutické užití MeSH
- inhibitory proteinkinas farmakologie chemie terapeutické užití MeSH
- lidé MeSH
- mTOR inhibitory farmakologie terapeutické užití MeSH
- protoonkogenní proteiny c-akt * metabolismus antagonisté a inhibitory MeSH
- sarkom * farmakoterapie metabolismus patologie MeSH
- signální transdukce * účinky léků MeSH
- TOR serin-threoninkinasy * antagonisté a inhibitory metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Prominin-1 (CD133) is a cholesterol-binding membrane glycoprotein selectively associated with highly curved and prominent membrane structures. It is widely recognized as an antigenic marker of stem cells and cancer stem cells and is frequently used to isolate them from biological and clinical samples. Recent progress in understanding various aspects of CD133 biology in different cell types has revealed the involvement of CD133 in the architecture and dynamics of plasma membrane protrusions, such as microvilli and cilia, including the release of extracellular vesicles, as well as in various signaling pathways, which may be regulated in part by posttranslational modifications of CD133 and its interactions with a variety of proteins and lipids. Hence, CD133 appears to be a master regulator of cell signaling as its engagement in PI3K/Akt, Src-FAK, Wnt/β-catenin, TGF-β/Smad and MAPK/ERK pathways may explain its broad action in many cellular processes, including cell proliferation, differentiation, and migration or intercellular communication. Here, we summarize early studies on CD133, as they are essential to grasp its novel features, and describe recent evidence demonstrating that this unique molecule is involved in membrane dynamics and molecular signaling that affects various facets of tissue homeostasis and cancer development. We hope this review will provide an informative resource for future efforts to elucidate the details of CD133's molecular function in health and disease.
Non-small cell lung cancer (NSCLC) is largely promoted by a multistep tumorigenesis process involving various genetic and epigenetic alterations, which essentially contribute to the high incidence of mortality among patients with NSCLC. Clinical observations revealed that NSCLC also co-opts a multifaceted immune checkpoint dysregulation as an important driving factor in NSCLC progression and development. For example, a deregulated PI3K/AKT/mTOR pathway has been noticed in 50-70% of NSCLC cases, primarily modulated by mutations in key oncogenes such as ALK, EGFR, KRAS, and others. Additionally, genetic association studies containing patient-specific factors and local reimbursement criteria expose/reveal mutations in EGFR/ALK/ROS/BRAF/KRAS/PD-L1 proteins to determine the suitability of available immunotherapy or tyrosine kinase inhibitor therapy. Thus, the expression of such checkpoints on tumors and immune cells is pivotal in understanding the therapeutic efficacy and has been extensively studied for NSCLC treatments. Therefore, this review summarizes current knowledge in NSCLC tumorigenesis, focusing on its genetic and epigenetic intricacies, immune checkpoint dysregulation, and the evolving landscape of targeted therapies. In the context of current and future therapies, we emphasize the significance of antibodies targeting PD-1/PD-L1 and CTLA-4 interactions as the primary therapeutic strategy for immune system reactivation in NSCLC. Other approaches involving the promising potential of nanobodies, probodies, affibodies, and DARPINs targeting immune checkpoints are also described; these are under active research or clinical trials to mediate immune regulation and reduce cancer progression. This comprehensive review underscores the multifaceted nature, current state and future directions of NSCLC research and treatment.
- MeSH
- antigeny CD274 metabolismus MeSH
- erbB receptory metabolismus MeSH
- fosfatidylinositol-3-kinasy metabolismus MeSH
- karcinogeneze MeSH
- lidé MeSH
- nádorová transformace buněk MeSH
- nádory plic * farmakoterapie genetika MeSH
- nemalobuněčný karcinom plic * farmakoterapie genetika MeSH
- protoonkogenní proteiny p21(ras) MeSH
- tyrosinkinasové receptory metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
OBJECTIVE: The insulin/IGF superfamily is conserved across vertebrates and invertebrates. Our team has identified five viruses containing genes encoding viral insulin/IGF-1 like peptides (VILPs) closely resembling human insulin and IGF-1. This study aims to characterize the impact of Mandarin fish ranavirus (MFRV) and Lymphocystis disease virus-Sa (LCDV-Sa) VILPs on the insulin/IGF system for the first time. METHODS: We chemically synthesized single chain (sc, IGF-1 like) and double chain (dc, insulin like) forms of MFRV and LCDV-Sa VILPs. Using cell lines overexpressing either human insulin receptor isoform A (IR-A), isoform B (IR-B) or IGF-1 receptor (IGF1R), and AML12 murine hepatocytes, we characterized receptor binding, insulin/IGF signaling. We further characterized the VILPs' effects of proliferation and IGF1R and IR gene expression, and compared them to native ligands. Additionally, we performed insulin tolerance test in CB57BL/6 J mice to examine in vivo effects of VILPs on blood glucose levels. Finally, we employed cryo-electron microscopy (cryoEM) to analyze the structure of scMFRV-VILP in complex with the IGF1R ectodomain. RESULTS: VILPs can bind to human IR and IGF1R, stimulate receptor autophosphorylation and downstream signaling pathways. Notably, scMFRV-VILP exhibited a particularly strong affinity for IGF1R, with a mere 10-fold decrease compared to human IGF-1. At high concentrations, scMFRV-VILP selectively reduced IGF-1 stimulated IGF1R autophosphorylation and Erk phosphorylation (Ras/MAPK pathway), while leaving Akt phosphorylation (PI3K/Akt pathway) unaffected, indicating a potential biased inhibitory function. Prolonged exposure to MFRV-VILP led to a significant decrease in IGF1R gene expression in IGF1R overexpressing cells and AML12 hepatocytes. Furthermore, insulin tolerance test revealed scMFRV-VILP's sustained glucose-lowering effect compared to insulin and IGF-1. Finally, cryo-EM analysis revealed that scMFRV-VILP engages with IGF1R in a manner closely resembling IGF-1 binding, resulting in a highly analogous structure. CONCLUSIONS: This study introduces MFRV and LCDV-Sa VILPs as novel members of the insulin/IGF superfamily. Particularly, scMFRV-VILP exhibits a biased inhibitory effect on IGF1R signaling at high concentrations, selectively inhibiting IGF-1 stimulated IGF1R autophosphorylation and Erk phosphorylation, without affecting Akt phosphorylation. In addition, MFRV-VILP specifically regulates IGF-1R gene expression and IGF1R protein levels without affecting IR. CryoEM analysis confirms that scMFRV-VILP' binding to IGF1R is mirroring the interaction pattern observed with IGF-1. These findings offer valuable insights into IGF1R action and inhibition, suggesting potential applications in development of IGF1R specific inhibitors and advancing long-lasting insulins.
- MeSH
- elektronová kryomikroskopie MeSH
- exprese genu MeSH
- fosfatidylinositol-3-kinasy metabolismus MeSH
- fosforylace MeSH
- insulinu podobný růstový faktor I * genetika metabolismus MeSH
- inzulin metabolismus MeSH
- lidé MeSH
- myši MeSH
- protein - isoformy metabolismus MeSH
- protoonkogenní proteiny c-akt metabolismus MeSH
- receptor IGF typ 1 * genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Neonatal hypoxic-ischemic encephalopathy (HIE) is a disease caused by insufficient blood supply in the brain in newborns during the perinatal period. Severe HIE leads to patient death, and patients with mild HIE are at increased risk of cognitive deficits and behavioral abnormalities. The NMDA receptor is an important excitatory receptor in the central nervous system, and in adult hypoxic-ischemic injury both subtypes of the NMDA receptor play important but distinct roles. The GluN2A-containing NMDA receptor (GluN2A-NMDAR) could activate neuronal protective signaling pathway, while the GluN2B-NMDAR subtype is coupled to the apoptosis-inducing signaling pathway and leads to neuronal death. However, the expression level of GluN2B is higher in newborns than in adults, while the expression of GluN2A is lower. Therefore, it is not clear whether the roles of different NMDA receptor subtypes in HIE are consistent with those in adults. We investigated this issue in this study and found that in HIE, GluN2B plays a protective role by mediating the protective pathway through binding with PSD95, which is quite different to that in adults. The results of this study provided new theoretical support for the clinical treatment of neonatal hypoxic ischemia.
- MeSH
- apoptóza MeSH
- fosfatidylinositol-3-kinasy metabolismus MeSH
- ischemie MeSH
- lidé MeSH
- mozková hypoxie a ischemie * metabolismus MeSH
- novorozenec MeSH
- protoonkogenní proteiny c-akt metabolismus MeSH
- receptory N-methyl-D-aspartátu metabolismus MeSH
- signální transdukce MeSH
- těhotenství MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease that exhibits constitutive activation of phosphoinositide 3-kinase (PI3K) driven by chronic B-cell receptor signaling or PTEN deficiency. Since pan-PI3K inhibitors cause severe side effects, we investigated the anti-lymphoma efficacy of the specific PI3Kβ/δ inhibitor AZD8186. We identified a subset of DLBCL models within activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL that were sensitive to AZD8186 treatment. On the molecular level, PI3Kβ/δ inhibition decreased the pro-survival NF-κB and AP-1 activity or led to downregulation of the oncogenic transcription factor MYC. In AZD8186-resistant models, we detected a feedback activation of the PI3K/AKT/mTOR pathway following PI3Kβ/δ inhibition, which limited AZD8186 efficacy. The combined treatment with AZD8186 and the mTOR inhibitor AZD2014 overcame resistance to PI3Kβ/δ inhibition and completely prevented outgrowth of lymphoma cells in vivo in cell line- and patient-derived xenograft mouse models. Collectively, our study reveals that subsets of DLBCLs are addicted to PI3Kβ/δ signaling and thus identifies a previously unappreciated role of the PI3Kβ isoform in DLBCL survival. Furthermore, our data demonstrate that combined targeting of PI3Kβ/δ and mTOR is effective in all major DLBCL subtypes supporting the evaluation of this strategy in a clinical trial setting.
- MeSH
- difúzní velkobuněčný B-lymfom * patologie MeSH
- fosfatidylinositol-3-kinasy * metabolismus MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- signální transdukce MeSH
- TOR serin-threoninkinasy metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Oxidative stress and autophagy are potential mechanisms associated with cerebral ischemia/reperfusion injury (IRI) and is usually linked to inflammatory responses and apoptosis. Curcumin has recently been demonstrated to exhibit anti-inflammatory, anti-oxidant, anti-apoptotic and autophagy regulation properties. However, mechanism of curcumin on IRI-induced oxidative stress and autophagy remains not well understood. We evaluated the protective effects and potential mechanisms of curcumin on cerebral microvascular endothelial cells (bEnd.3) and neuronal cells (HT22) against oxygen glucose deprivation/reoxygenation (OGD/R) in vitro models that mimic in vivo cerebral IRI. The cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) activity assays revealed that curcumin attenuated the OGD/R-induced injury in a dose-specific manner. OGD/R induced elevated levels of inflammatory cytokines TNF-alpha, IL-6 as well as IL-1beta, and these effects were notably reduced by curcumin. OGD/R-mediated apoptosis was suppressed by curcumin via upregulating B-cell lymphoma-2 (Bcl-2) and downregulating Bcl-associated X (Bax), cleaved-caspase3 and TUNEL apoptosis marker. Additionally, curcumin increased superoxide dismutase (SOD) and glutathione (GSH), but suppressed malondialdehyde (MDA) and reactive oxygen species (ROS) content. Curcumin inhibited the levels of autophagic biomarkers such as LC3 II/LC3 I and Beclin1. Particularly, curcumin induced p62 accumulation and its interactions with keap1 and promoted NF-E2-related factor 2 (Nrf2) translocation to nucleus, accompanied by increased NADPH quinone dehydrogenase (Nqo1) and heme oxygenase 1 (HO-1). Treatment of curcumin increased phosphorylation-phosphatidylinositol 3 kinase (p-PI3K) and p-protein kinase B (p-AKT). The autophagy inhibitor 3-methyladenine (3-MA) activated the keap-1/Nrf2 and PI3K/AKT pathways. This study highlights the neuroprotective effects of curcumin on cerebral IRI.
- MeSH
- antioxidancia farmakologie metabolismus MeSH
- autofagie fyziologie MeSH
- endoteliální buňky metabolismus MeSH
- faktor 2 související s NF-E2 metabolismus MeSH
- fosfatidylinositol-3-kinasy metabolismus MeSH
- KEAP-1 metabolismus MeSH
- kurkumin * farmakologie MeSH
- kyslík metabolismus MeSH
- neuroprotektivní látky * farmakologie MeSH
- oxidační stres MeSH
- protoonkogenní proteiny c-akt metabolismus MeSH
- signální transdukce MeSH
- Publikační typ
- časopisecké články MeSH
Intestinal epithelial differentiation is a highly organised process. It is influenced by a variety of signalling pathways and enzymes, such as the PI3K pathway and soluble epoxide hydrolase (sEH) from arachidonic acid metabolism. We investigated the changes in the expression of enzymes and lipid messenger from the PI3K pathway, including PTEN, during intestinal cell differentiation in vitro using HT-29 and Caco2 cells and compared them with immunohistochemical patterns of these proteins in human colon. To investigate the possible crosstalk between the PI3K pathway and sEH, we treated HT-29 and Caco2 cells with the sEH inhibitor TPPU. Administration of TPPU to differentiated cells decreased the expression of PTEN, thus reversing the change in its expression observed during cell differentiation. In addition, multiplex immunofluorescence staining confirmed the relationship between the expression of PTEN and villin, a marker of intestinal cell differentiation, ranging from a moderate correlation in undifferentiated cells to a very strong correlation in differentiated cells treated with TPPU. Furthermore, we confirm that PTEN and sEH mirrored their expression patterns in samples of prenatal and adult human intestine compared to tumours using immunohistochemical staining. Taken together, it appears that PTEN and sEH cooperate in the process of intestinal cell differentiation. A better understanding of the crosstalk between the PI3K pathway and sEH and its consequences for cell differentiation is highly desirable, as several sEH inhibitors are under clinical investigation for the treatment of various diseases.
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.
- MeSH
- 1-fosfatidylinositol-3-kinasa * metabolismus terapeutické užití MeSH
- fosfatidylinositol-3-kinasy metabolismus MeSH
- inhibitory fosfoinositid-3-kinasy farmakologie MeSH
- inhibitory proteinkinas farmakologie terapeutické užití MeSH
- lidé MeSH
- nádory * farmakoterapie MeSH
- protoonkogenní proteiny c-akt metabolismus MeSH
- TOR serin-threoninkinasy metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
