Akt Inhibitor Research Articles

MYBL2 promotes cell proliferation and inhibits cell apoptosis via PI3K/AKT and BCL2/BAX/Cleaved-caspase-3 signaling pathway in gastric cancer cells

The transcription factor MYB proto-oncogene like 2 (MYBL2) has been reported to be involved in the occurrence and development of various tumors, however, its role in gastric cancer (GC) remains to be elucidated. In this study, the Kaplan-Meier plotter was used to evaluate the prognostic value of different MYBL2 expression levels in GC patients. The UALCAN database were applied to analyze the relationships between MYBL2 and clinicopathological characteristics of GC. GC cell proliferation, cell cycle and apoptosis were determined by CCK-8 and flow cytometry assays, and proteins were examined by Western blot analysis. Next, signaling pathway enrichment analysis of MYBL2-related genes and protein expression were analyzed by Gene Set Enrichment Analysis (GSEA) and Western blot assays. The results found that MYBL2 expression was significantly upregulated in GC compared with adjacent non-malignant tissues and associated with poor patient survival, tumor, stages and lymph node metastasis. Forced expression of MYBL2 could promote cell proliferation, resulting in an accelerated S phase progression and inhibiting cell apoptosis in GC cells. Conversely, MYBL2 silencing inhibited cell proliferation, induced G2/M phase arrest and promoted cell apoptosis in GC cells. Mechanistically, Western blot analysis showed that MYBL2 silencing decreased the expression of BCL2 and upregulated the expression of Cleaved-caspase-3 and BAX in HGC-27 cells. Conversely, MYBL2 overexpression in AGS cells resulted in the opposite effects. Furthermore, enforced expression of MYBL2 activated the PI3K/AKT signaling pathway, especially AKT phosphorylation. Additionally, the AKT inhibitor MK2206 significantly reversed the proliferation capacity of GC cells induced by MYBL2 overexpression. Therefore, these results suggest that upregulated expression of MYBL2 contributes to GC cell growth and inhibits cell apoptosis by regulating the PI3K/AKT and BCL2/BAX/Cleaved-caspase-3 signaling pathways in GC cells indicating that MYBL2 may be a new therapeutic target and prognostic marker for GC.

Topoisomerase inhibitor amonafide enhances defense responses to promote longevity in C. elegans.

Aging is a major risk factor for disease, and developing effective pharmaceutical interventions to improve healthspan and promote longevity has become a high priority for society. One of the molecular pathways related to longevity in various model organisms revolves around lowering AKT1 levels. This prompted our in silico drug screen for small molecules capable of mimicking the transcriptional effects of AKT1 knockdown. We found topoisomerase inhibitors as a top candidate longevity-drug class. Evaluating multiple compounds from this class in C. elegans revealed that the topoisomerase inhibitor amonafide has the greatest benefit on healthspan and lifespan. Intriguingly, the longevity effect of amonafide was not solely dependent on DAF-16/FOXO, the canonical pathway for lifespan extension via AKT1 inhibition. We performed RNA-seq on amonafide-treated worms and revealed a more youthful transcriptional signature, including the activation of diverse molecular and cellular defense pathways. We found the mitochondrial unfolded protein response (UPRmt) regulator afts-1 to be crucial for both improved healthspan and extended lifespan upon amonafide treatment. Moreover, healthspan was partially dependent on the immune response transcription factor zip-2 and the integrated stress response transcription factor atf-4. We further examined the potential of amonafide in age-related disease. Treating a C. elegans model for Parkinson's disease with amonafide improved mobility. In conclusion, we identified amonafide as a novel geroprotector, which activates mitochondrial-, pathogen-, and xenobiotic-associated defense responses that-though more studies are needed-may serve as a candidate for Parkinson's disease therapy.

Discovery of YJZ5118: A Potent and Highly Selective Irreversible CDK12/13 Inhibitor with Synergistic Effects in Combination with Akt Inhibition.

Cyclin-dependent kinases 12 and 13 (CDK12/13) have emerged as promising therapeutic targets for castration-resistant prostate cancer (CRPC) and other human cancers. Despite the development of several CDK12/13 inhibitors, challenges remain in achieving an optimal balance of potency, selectivity and pharmacokinetic properties. Here, we report the discovery of YJZ5118, a novel, potent and highly selective covalent inhibitor of CDK12/13 with reasonable pharmacokinetic profiles. YJZ5118 effectively inhibited CDK12 and CDK13 with IC50 values of 39.5 and 26.4 nM, respectively, while demonstrating high selectivity over other CDKs. Mass spectrometry analysis, cocrystal structure determination, and pulldown-proteomic experiments confirmed the compound's covalent binding mode with CDK12/13. Functionally, YJZ5118 efficiently suppressed the transcription of DNA damage response genes, induced DNA damage, and triggered apoptosis. Moreover, the compound significantly inhibited the proliferation of multiple tumor cell lines, particularly prostate cancer cells. Notably, YJZ5118 exhibited synergistic effects with Akt inhibitors both in vitro and in vivo.

Akt inhibition is effective against PTEN-deleted, chemoirradiation-resistant glioblastoma stem cells

Activated Akt and loss of phosphatase and tensin homolog (PTEN) tumour suppression aid chemo- and radio-resistance in glioblastoma stem cells (GSC), contributing to treatment failure in glioblastoma. In this study, sixteen GSC lines were generated from 66 individual glioma samples, in gliomasphere culture conditions. Thirteen of 16 GSC lines expressed hyperphosphorylated Akt (Ser473); Akt phosphorylation did not correlated with EGFR expression. An LDH colorimetric assay was used to measure the in vitro cytotoxicity of eight of these lines. Akt X (20 µM) proved more effective at inducing in vitro GSC cytotoxicity (range: 22-73%) over 48 hours than triciribine (20 µM) (0-27%), although both agents inhibited Akt phosphorylation as detected by western blot analysis. A statistically significant correlation between PTEN loss (western blot) and the extent of Akt X-induced cytotoxicity was found (p = 0.03). Akt inhibition reduces in vitro proliferation of treatment-resistant GSC lines, especially in PTEN-deficient lines, warranting further translational investigation in glioblastoma.

Regulatory dynamics of Nanog in chondrocyte dedifferentiation: role of KLF4/p53 and p38/AKT signaling.

Homeobox protein Nanog, a member of the transcription factor family, plays a crucial role in maintaining the pluripotency and self-renewal of embryonic stem cells. Due to its diverse activities, Nanog has been identified in multiple cell types, including embryonic stem cells (ESCs) and cancer stem cells (CSCs). However, its molecular mechanism in chondrocytes remains unclear. In this study, we explored the effects of Nanog on chondrocytes and its interaction with chondrocyte-specific proteins. Chondrocytes were transfected with a Nanog cDNA vector, resulting in reduced expression of the chondrogenic markers Type II collagen and SOX9, as confirmed by western blot, RT-PCR, and immunofluorescence. Following siRNA transfection, the dedifferentiation effect of Nanog was reversed, restoring Type II collagen and SOX9 expression. We also discovered that the mechanism by which Nanog affects chondrocytes is closely linked to p53 and KLF4. Overexpression of KLF4 induced the phosphorylation of p53, and phospho-p53 directly inhibited Nanog expression. Moreover, the p53 activator Nutlin-3A accelerated Nanog degradation, while the p53 inhibitor Pifithrin-α stabilized Nanog. Stabilized Nanog continued to promote chondrocyte dedifferentiation. Additional experiments were performed to identify the signaling pathways involved in Nanog-induced chondrocyte dedifferentiation. Our results showed that Nanog overexpression in chondrocytes significantly impacted the p38 kinase and AKT signaling pathways. Inhibition of p38 and AKT with SB203580 and LY294002 reduced Nanog expression and partially restored Type II collagen levels. Conversely, activation with anisomycin(ANS) and 740 Y-P enhanced Nanog expression, further reducing Type II collagen levels. To investigate Nanog's role in early development in vivo, we injected Nanog expression vectors into zebrafish embryos. The injected zebrafish exhibited structural defects in craniofacial cartilage, confirming Nanog's involvement in chondrocyte differentiation. These findings suggest that Nanog induces chondrocyte dedifferentiation, and this process can be modulated via the p53/KLF4 and p38/AKT pathways.

Apoptotic breast cancer cells after chemotherapy induce pro-tumour extracellular vesicles via LAP-competent macrophages.

Apoptotic breast cancer cells after chemotherapy induce pro-tumour extracellular vesicles via LAP-competent macrophages.

Neoadjuvant Strategies for Triple Negative Breast Cancer: Current Evidence and Future Perspectives

ABSTRACTTriple‐negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer, characterized by poor prognosis and limited therapeutic options. Although neoadjuvant chemotherapy (NACT) remains the established treatment approach, its suboptimal efficacy associated with TNBC highlight the urgent need for optimized treatment strategies to improve pathological complete response (pCR) rates. This review provides a comprehensive overview of recent advancements in neoadjuvant treatment for TNBC, emphasizing pivotal breakthroughs in therapeutic strategies and the ongoing pursuit of innovative approaches to enhance precision medicine. It emphasizes the clinical value of platinum‐based agents, such as carboplatin and cisplatin, which have shown significant improvements in pCR rates, particularly in TNBC patients with BRCA mutations. Additionally, the review explores progress in targeted therapies, including PARP inhibitors, AKT inhibitors, and Antiangiogenic agents, showcasing their potential for personalized treatment approaches. The integration of immunotherapy, particularly immune checkpoint inhibitor like pembrolizumab and atezolizumab, with chemotherapy has demonstrated substantial efficacy in high‐risk TNBC cases. Future research priorities include refining biomarker‐driven strategies, optimizing therapeutic combinations, developing antibody‐drug conjugates (ADCs) targeting TROP2 and other biomarkers, and reducing treatment‐related toxicity to develop safer and highly personalized neoadjuvant therapies. Furthermore, artificial intelligence has also emerged as a transformative tool in predicting treatment response and optimizing therapeutic decision‐making in TNBC. These advancements aim to improve long‐term outcomes and quality of life for patients with TNBC.

Integrating network pharmacology to investigate the mechanism of quercetin's action through AKT inhibition in co-expressed genes associated with polycystic ovary syndrome and endometrial cancer.

Integrating network pharmacology to investigate the mechanism of quercetin's action through AKT inhibition in co-expressed genes associated with polycystic ovary syndrome and endometrial cancer.

Capivasertib enhances chimeric antigen receptor Tcell activity in preclinical models of B cell lymphoma.

Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling is involved in the growth of normal and cancer cells and is crucial for Tcell activation. Previously, we have shown that AKT Inhibitor VIII, a selective AKT-1/2 inhibitor, during chimeric antigen receptor (CAR) Tcell manufacturing, improves CAR Tcell function in preclinical models. Although AKT Inhibitor VIII could enhance CAR Tcell function, AKT Inhibitor VIII is not a clinical-grade compound. However, pan-AKT inhibitors have been applied against cancers with PIK3CA/AKT/PTEN alterations in clinical trials. We evaluated exvivo and invivo strategies of enhancing CAR Tcell therapeutic effect using the pan-AKT inhibitor capivasertib. We found that exvivo 0.25μM capivasertib treatment during the period of Tcell stimulation during manufacture enhanced the antitumor activity of CAR Tcells in B cell lymphoma mouse models. Mechanistically, capivasertib changed gene and protein expression patterns related to the functions of memory and effector CAR Tcells. Furthermore, invivo combination therapy of capivasertib and CD19-specific CAR Tcells led to improved early response to and persistence of functional CAR Tcells in mice bearing PTEN-deficient lymphoma cells compared to CAR Tcells alone. Capivasertib exerts a similar function to AKT Inhibitor VIII in modulating CAR Tcells, and combining CAR Tcell therapy with capivasertib both exvivo and invivo offers the potential to improve patient outcomes. Since PTEN deficiency is common in cancer and is the main mechanism for capivasertib function, combination therapy may provide an alternative solution for the challenges of CAR Tcell therapy.

5,7-Dihydroxy-4-Methylcoumarin enhances osteogenesis and ameliorates osteoporosis via the AKT1 pathway.

5,7-Dihydroxy-4-Methylcoumarin enhances osteogenesis and ameliorates osteoporosis via the AKT1 pathway.

Dentin sialoprotein promotes endothelial differentiation of dental pulp stem cells through DSPaa34-50-endoglin-AKT1 axis.

Dentin sialoprotein promotes endothelial differentiation of dental pulp stem cells through DSPaa34-50-endoglin-AKT1 axis.

A Computational Journey in Anticancer Drug Discovery: Exploring AKT1 Inhibition by Novel Oxadiazoles Using Molecular Docking, ADMET, Density Functional Theory and Molecular Dynamic Simulation

A Computational Journey in Anticancer Drug Discovery: Exploring AKT1 Inhibition by Novel Oxadiazoles Using Molecular Docking, ADMET, Density Functional Theory and Molecular Dynamic Simulation

Effects of c-Kit Receptor, AKT, and NF-κB Inhibitors on Immune Evasion in Multiple Myeloma Cells.

Up-regulation of immune checkpoint ligands and secretion of soluble factors in the tumor microenvironment led to the survival of cancerous plasma cells in the bone marrow milieu. Therefore, we investigate the relationship between the inhibition of c-Kit receptor, AKT, and NF-κB signaling pathways and the regulation of immune escape mechanisms in multiple myeloma. The U266B1 cell line was treated with Masitinib as a c-Kit receptor inhibitor, Perifosine as AKT inhibitor, and Bortezomib as NF-κB inhibitor either in single or combined form. Apoptosis and cell viability were evaluated using flow cytometry and MTT assays, respectively. The relative expression of programmed death-ligand 1 (PD-L1), poliovirus receptor (PVR), and interleukin 6 (IL-6) were determined by real-time PCR. Also, the secretion of IL-6 was measured by ELISA. Our findings demonstrated decreased proliferation of U266B1 cells after co-treatment with Masitinib, Perifosine, and Bortezomib. An increase in apoptosis was observed in the co-treatment of Masitinib and Perifosine. Furthermore, results elucidated that the expression of PD-L1 and IL-6 decreased after treatment with Masitinib, Perifosine, and Bortezomib in both single and co-treatments. Regarding PVR, combined treatment of U266B1 cells with Masitinib, Perifosine, and Bortezomib decreased the expression level of PVR. We showed that c-Kit receptor, AKT, and NF-κB pathway inhibitors not only serve as cytotoxic drugs but also inhibit the immune escape mechanisms of malignant plasma cells by disrupting signaling pathways.

Glioblastoma- derived exosomes (GBM-Exo) regulate microglial M2 polarization via the RAC1/AKT/NRF2 pathway.

The impact of exosome-mediated communication between glioblastoma and microglia on the formation of an immunosuppressive microenvironment remains to be explored. Tumor-associated macrophages are more likely to adopt an M2-like phenotype within the immunosuppressive environment. Here, we investigate the molecular mechanisms by which glioblastoma-derived exosomes promote microglial M2 polarization through RAC1. The expression of RAC1 in GBM was collected from public databases. A C57BL/6 mouse glioma xenograft model was established using intracranial stereotactic injection. RAC1 expression was validated by qRT-PCR, Western blotting, and immunohistochemistry. Glioblastoma-derived exosomes were isolated by ultracentrifugation and characterized by Nanoparticle Tracking Analysis (NTA), transmission electron microscopy, and Western blotting for exosome markers, with the content of RAC1 being profiled. RAC1 and AKT inhibitors were used to co-treat microglia with exosomes. Microglial polarization under different treatment conditions was assessed by Western blotting and immunofluorescence. Our study reveals that RAC1 is aberrantly expressed in glioblastoma and is associated with macrophage immune infiltration. GBM-derived exosomes, carrying RAC1, promote the M2 polarization of microglia. In microglia treated with GBM-derived exosomes, inhibition of RAC1 activity suppressed AKT phosphorylation and NRF2 nuclear translocation, while reducing the expression of M2 phenotype markers. Notably, following AKT inhibition, the exosome-induced NRF2 nuclear translocation was also significantly suppressed, highlighting the critical role of RAC1-mediated AKT activation in NRF2 translocation and microglial M2 polarization. Our study demonstrates that RAC1-carrying GBM-exosomes promote M2 polarization of microglia, a process mediated through the RAC1/AKT/NRF2 pathway.

Cytotoxicity of Blumea balsamifera on A549 Lung Cancer Cells: Integrating in Vitro Analysis with Computational Study of AKT-1 Inhibition

Cytotoxicity of Blumea balsamifera on A549 Lung Cancer Cells: Integrating in Vitro Analysis with Computational Study of AKT-1 Inhibition

Akt2 inhibition alleviates temporomandibular joint osteoarthritis by preventing subchondral bone loss

BackgroundThis study aimed to investigate the role and mechanism of the Akt2 pathway in different stages of anterior disc displacement (ADD)-induced temporomandibular joint osteoarthritis (TMJOA).MethodsA rat model for TMJOA that simulates anterior disc displacement was established. For inhibit Akt2 expression in subchondral bone, rats were intravenously injected with adeno-associated virus carrying Akt2 shRNA at a titer of 1 × 1012 transducing units/mL 10 days before the ADD or sham operations. The rats were euthanized and evaluated 1 or 8 weeks after surgery, as these time points represented the early or advanced stage of ADD. Immunostaining was performed to examine the expression and location of phosphorylated Akt2 in different stages of ADD. Microcomputed tomography, hematoxylin and eosin staining, toluidine blue staining, Western blotting, immunohistochemical and immunofluorescence staining were used to elucidate the pathological changes and potential mechanisms underlying ADD-induced TMJOA.ResultsIn the rat model of ADD-induced TMJOA, rapid condylar bone loss occurred with increased phosphorylation of Akt2 in subchondral bone macrophages within 1 week post-surgery. At 8 weeks after surgery, abnormal remodeling of subchondral bone and degenerative changes in cartilage were observed. Inhibiting Akt2 reduced condylar bone resorption following ADD surgery while improving condylar bone morphology at 8 weeks post-surgery. Additionally, inhibition of Akt2 alleviated cartilage degeneration characterized by a decreased number of apoptotic chondrocytes, reduced expression of matrix metalloproteinases, and increased collagen type II expression in cartilage tissue.ConclusionsThe Akt2 pathway is activated mainly in subchondral bone macrophages during the early stage of ADD and plays an important role in regulating subchondral bone remodeling. Inhibition of Akt2 could serve as a prophylactic treatment to slow the progression of ADD-induced TMJOA.

The Emerging Role and Clinical Significance of PI3K-Akt-mTOR in Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is a common soft tissue sarcoma primarily affecting children and young adults. This disease is more prevalent in children under 15, with two main types: embryonal Rhabdomyosarcoma (eRMS), which has a better prognosis, and alveolar Rhabdomyosarcoma (aRMS), which is more aggressive and associated with specific genetic alterations. The PI3K-Akt-mTOR pathway is often hyperactivated in RMS, contributing to cell proliferation, survival, and resistance to therapies. The presence of phosphorylated components of this pathway correlates with poor survival outcomes. Here, we discuss various therapeutic approaches targeting the PI3K-Akt-mTOR pathway. These include the use of specific inhibitors (e.g., PI3K inhibitors, Akt inhibitors) and combination therapies that may enhance treatment efficacy. Dietary supplements like curcumin and repurposed drugs such as chloroquine are also mentioned for their potential to induce apoptosis in RMS cells. We also emphasize the need for innovative strategies to improve survival rates, which have remained stagnant over the years. Targeting super-enhancers and transcription factors associated with RMS may provide new therapeutic avenues. Overall, this review underscores the critical role of the PI3K-Akt-mTOR pathway in RMS and the potential for targeted therapies to improve patient outcomes.

A Promising Resveratrol Analogue Suppresses CSCs in Non-Small-Cell Lung Cancer via Inhibition of the ErbB2 Signaling Pathway.

The ErbB2 signaling pathway plays a crucial role in cancer stem cells (CSCs), governing cancer aggressiveness and proliferation. Targeting ErbB2 holds promise for advancing cancer therapeutics. Resveratrol (RES) and its derivatives have been noted for their ability to target proteins that are involved in CSCs. In this investigation, we synthesize novel derivatives of RES, aim at elucidating structure-activity relationships (SARs) that could enhance the anticancer properties of the RES analogues, and explore their capacities to suppress CSCs. YI-12, an O-benzyl-substituted 1,3-diphenylpropane, demonstrated the most potent anticancer activity against lung cancer cells (A549 and H460), showing high potential inhibiting cancer colony formation. Interestingly, not only does YI-12 suppress CSCs-related proteins, indicated by decreased expression of CSC-enhancing molecules such as CD133-, OCT4-, and CSC-related protein β-catenin, but it also induces apoptosis in CSC-rich spheroids after treatment. Additionally, molecular docking and bioinformatic analysis suggest ErbB2 as a potential target of the compound with a strong binding affinity (-6.709 kcal/mol) compared to the reference compound TAK-285 (-5.563 kcal/mol). YI-12's capability to bind and inhibit ErbB2 leads to the suppression of PI3K and AKT. In conclusion, we highlight the novel resveratrol derivative YI-12 for its ability to inhibit CSCs through the ErbB2 signaling pathway. This compound represents a promising structure that should be further developed for potential use in anticancer therapy.

Targeting AKT as a promising strategy for SOX2-positive, chemoresistant osteosarcoma

Osteosarcoma (OS) is the most prevalent type of primary malignant bone cancer and currently lacks effective targeted treatments. Increasing evidence indicates that SOX2 overexpression is a primary driver of OS. By screening a small-molecule kinase inhibitor library, we identified AKT as a kinase essential for robust SOX2 expression in OS cells. AKT was found to be frequently overexpressed in OS and positively correlated with SOX2 protein levels. We demonstrated that AKT has no effect on SOX2 transcription but promotes SOX2 protein stability. Mechanistically, AKT binds to and phosphorylates SOX2 at T116, preventing SOX2 ubiquitination and proteasome-dependent degradation by ubiquitin E3 ligases UBR5 and STUB1. Moreover, we found that AKT-SOX2 axis is a significant modulator of cancer stemness and chemoresistance and that the combination of AKT inhibitor MK2206 and cisplatin resulted in a synergistic and potent inhibition of OS tumor growth in the PDX model. In conclusion, we identified a critical role for AKT in promoting SOX2 overexpression, tumor stemness, and chemoresistance in OS, and provided evidence that targeting AKT combined with chemotherapy may hold promise for treating refractory OS.Working model showing that AKT stabilizes SOX2 by phosphorylating T116 site. Phosphorylation by AKT restraints the binding and ubiquitinoylation of SOX2 by the UBR5 and STUB1, thus promoting SOX2 stability and tumorigenic activity. Targeting AKT by MK2206 inhibits T116 phosphorylation and promotes SOX2 ubiquitination pathway, which impairs SOX2 tumorigenic activity. A combined treatment with chemo reagent and AKT inhibitor could achieve better therapeutic effect for SOX2-positive OS.

AKT1 Phosphorylates FDX1 to Promote Cuproptosis Resistance in Triple-Negative Breast Cancer.

Cuproptosis, a recently defined copper-dependent cell death pathway, remains largely unexplored in tumor therapies, particularly in breast cancer. This study demonstrates that triple-negative breast cancer (TNBC) bears a relatively elevated copper levels and exhibits resistance to cuproptosis. Mechanistically, copper activates the AKT signaling pathway, which inhibits ferredoxin-1 (FDX1), a key regulator of cuproptosis. AKT1-mediated FDX1 phosphorylation not only abrogates FDX1-induced cuproptosis and aerobic respiration but also promotes glycolysis. Consequently, the combination of AKT1 inhibitors and the copper ionophores synergistically alleviate TNBC tumorigenesis both in vitro and in vivo. In summary, the findings reveal a crucial mechanism underlying TNBC resistance to cuproptosis and suggest a potential therapeutic approach for TNBC.