Overall, our study revealed that PDZK1 acts as a novel oncogene in glioma by binding to AKT1 and maintaining the activation of the AKT/mTOR signaling pathway. Thus, PDZK1 may be a potential therapeutic target for glioma.

No abstract available

The combination of HDW and AP targets 16 key genes to impede the development of NPC, primarily by modulating AKT1 and VEGFA pathways.

AnxA6 deSUMOylation contributes to HCC progression and EMT phenotype, and the combination of AnxA6 and SENP1 is a better tumor biomarker for diagnosis of HCC grade malignancy and prognosis.

Our finding revealed that local anesthetic ropivacaine attenuated breast cancer stemness through AKT1/GGT1/NF-κB signaling pathway, suggesting the potential clinical value of ropivacaine in breast cancer treatment.

We found that treatment with cholesterol-lowering drugs such as lovastatin and simvastatin promoted cell apoptosis in all RMS lines by reducing Akt1 and Cav1 levels and increasing intracellular ROS levels...Furthermore, in combination with the chemotherapeutic agent actinomycin D, statins were effective in reducing cell survival through increased apoptosis. Taken together, our findings suggest that the molecularly linked signature formed by Akt1, Src, Cav1, and catalase may represent a prognostic determinant for identifying subgroups of RMS patients with higher probability of recurrence after radiotherapy. Furthermore, statin-induced oxidative stress could represent a treatment option to improve the success of radiotherapy.

P2, N=60, Not yet recruiting, Zhejiang Haichang Biotech Co., Ltd.

Further, MD simulation and PCA analyses showed that the phytochemicals possessed significant binding efficacy with CC protein. These results point the way for more investigation into SHPE compound's potential as CC treatment.

Treatment with the conventional drug of choice AZD5363 (a pan AKT inhibitor) enhanced cell death and diminished HK2 levels in AKT1 mutants...By affecting metabolism, inflammation, and redox homeostasis AKT1-E17K confers a survival advantage in meningioma cells. Our findings suggest that targeting AKT-HK2 cross-talk to induce ROS-dependent cell death could be exploited as novel therapeutic approach in meningiomas.

Human melanoma samples with high IMP-3 levels also showed high HMGA2, AKT1 and RELA expression. Our results show that IMP-3 enhances melanoma cell migration through the regulation of the AKT1 and RELA axis.

Additionally, the expression of PLK4 protein exhibited a positive correlation with AKT1 phosphorylation in glioma patient tissues. These findings highlight the pivotal role of PLK4-mediated phosphorylation of AKT1 in glioma tumorigenesis and dysregulation of glucose metabolism.

Unlike mitochondrial ME2, which accounts for adjusting the tricarboxylic acid (TCA) cycle, ME2fl functions as a scaffold that brings together the key glycolytic enzymes phosphofructokinase (PFKL), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and pyruvate kinase M2 (PKM2), as well as Lactate dehydrogenase A (LDHA), to promote glycolysis in the cytosol. Thus, through phosphorylation of ME2fl, AKT1 enhances the glycolytic capacity of tumor cells in vitro and in vivo, revealing an unexpected role for subcellular translocation switching of ME2 mediated by AKT1 in the metabolic adaptation of tumor cells to growth stimuli.

Moreover, DHX9 was upregulated in tumors from PARPi-resistant BRCAm HGSOC patients, and high co-expression of DHX9 and AKT1 correlated with worse survival. Together, this study reveals an interaction between AKT1 and DHX9 that facilitates R-loop resolution and identifies combining ATRi and AKTi as a rational treatment strategy for BRCAm HGSOC irrespective of PARPi resistance status.

The average binding free energies for the Akt1-CQU, Akt1-Ipatasertib, and Akt1-Hit9 systems were - 34.44, - 63.37, and - 39.14 kJ mol, respectively. In summary, the results obtained in this investigation suggested that Hit9 with novel scaffold may be a promising lead compound for developing new Akt1 inhibitor for treatment of various cancers with Akt1 overexpressed.

The residual analysis demonstrated that allosteric and isoform-specific residues such as Trp80 and Val270 contributed the larger energy for ligand binding. The proposed integrated approach in this study might achieve a futuristic outcome when employed in a pharmaceutical scheme different from the conventional method.Communicated by Ramaswamy H. Sarma.

In human glioma samples, S100A9 expression was positively associated with CD206 expression, but negatively correlated with CD8+T lymphocyte accumulation in the TME. Our data indicated that glioma-derived S100A9 has a promising ability to manipulate non-malignant cells and promote immune evasion in the TME, providing valuable insight into the mechanism by which S100A9 participates in the progression of glioma.

Quercetin may mitigate doxorubicin-induced kidney injury in mice by regulating renal cell inflammatory factors and Raf/MEK/ERK signaling pathway through AKT1 to promote recovery of renal function.

In conclusion, CIP2A could interact with AKT1 to promote the malignant biological behaviors of OSCC cells by upregulating the GSK-3β/β-catenin pathway. These findings may provide a targeted therapy for OSCC treatment.

Of the 21 HER2-negative PDX models, DIACC3010 significantly inhibited the growth of 38%. Altogether, these results provide a path forward to validate the potential biomarkers of DIACC3010 sensitivity in GC and support clinical evaluation of DIACC3010 monotherapy and combination with trastuzumab in patients with HER2- negative and positive advanced GCs, respectively.

In summary, this is the first study to report that miR-143-3p overexpression in prostate cancer may inhibit EMT by targeting AKT1. The findings suggest miR-143-3p could be a useful diagnostic and prognostic biomarker for prostate cancer.

Cell viability assay indicated that induction of ferroptosis by GPX4/siRNA or FIN56 and apoptosis by Akt1/siRNA in resistant cell lines could reverse the oxaliplatin resistance. We concluded that downregulation of Akt1 or Gpx4 could increase the efficacy of oxaliplatin to overcome the resistance compared to FIN56.

(R,R)-59 is the first SETDB1 small-molecule positive activator for the methyltransferase activity of this protein. Mechanism of action studies show that full-length SETDB1 is required for significant in vitro methylation of an Akt1-K64 peptide and that this activity is stimulated by (R,R)-59 primarily through an increase in catalytic activity rather than a change in S-adenosyl methionine binding.

By CCK8 assay, we screened the compound D1-1 (IC = 0.10 μM) with the strongest inhibitory activity against H1975 cells, and its activity was 100 times higher than PPT (IC = 12.56 μM) and 300 times higher than gefitinib (IC = 32.15 μM)...Subsequent pharmacological experiments showed that D1-1 significantly inhibited the proliferation and metastasis of H1975 cells and slightly induced their apoptosis by inhibiting both tubulin polymerization and the AKT pathway activation. Collectively, these data demonstrate that the novel hybrid molecule D1-1 may be an excellent lead compound for the treatment of human NSCLC as a dual inhibitor of tubulin and AKT.

The impact of AKT1-knockout (AKT1_KO) and AKT-inhibition using Ipatasertib on MDA-MB-231 BR cells was assessed using in vitro cell proliferation and migration assays...AKT1-inhibition showed altered gene expression profile leading to modified cell migration, clonogenic survival and radioresistance in MDA-MB-231BR. We conclude, that AKT1-inhibition in combination with radiotherapy contribute to novel treatment strategies for breast cancer brain metastases.

Activation of AKT1 also mediated proteasomal degradation of DUSP2 via the AKT1/TRIM21 positive feedback loop. We propose increasing the level of DUSP2 as a potential therapeutic strategy for PDAC.

MyD88 may thus serve as a potential therapeutic target in PDAC. ST2825 may serve as a novel agent for the targeted therapy of PDAC in the future.

The 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay showed that after 24 hrs of exposure to piperine (15 µmol/ml), cell viability fell to 50% compared to the standard drug flutamide (SDF) (51 µmol/ml) with a lower IC concentration...The complementary charge between AKT1 and piperine was emphasized in the transient ligand-protein binding interaction in molecular dynamic modeling over 100 ns, and stable hydrogen bond interaction between Lys268 and Ser205 amino acid residues of the active pocket was hypothesized. Overall, the findings from our in vitro and MD simulations provide insights into the mechanism of piperine targeting AKT1 and offer a possible candidate for future prostate cancer therapeutic development.Communicated by Ramaswamy H. Sarma.

As the active component of the Yishen Tongluo Jiedu recipe, quercetin inhibited PCa development through the Akt1-related CXCL12/CXCR4 pathway. This study provided a new idea for PCa treatment and a theoretical basis for further research.

Subsequent MD simulations to verify the stability of chosen drugs to the Akt-1 allosteric site showed valganciclovir, dasatinib, indacaterol, and novobiocin to have high stability. Further, predictions for possible biological interactions were performed using computational tools such as ProTox-II, CLC-Pred, and PASSOnline. The shortlisted drugs open a new class of allosteric Akt-1 inhibitors for the therapy of NSCLC.

This study demonstrated that circ_0067997 functioned as a sponge of miR-615-5p to target AKT1 expression, thereby enhancing the growth and restricting the apoptosis of DDP-insensitive GC cells. These new findings offered a valuable target for the detection and management of GC.

Our data demonstrated for the first time the synergistic effect of a novel combination of KPT-330 and CX-4945 on cell growth arrest and apoptosis in AML cells, and identify the underlying mechanism bytargeting the PIK3CD/AKT1/FOXO3 signaling pathway, which highlighted the feasibility of clinical trials for combination therapy of AML patients.

Here, we found that DDP resistant ovarian cancer cells are more susceptible to Erastin induced ferroptosis. We further revealed that the loss of AKT1 was the reason for the increased autophagy level of DDP resistant ovarian cancer cells. Our study provides new insights into reversing DDP resistance in ovarian cancer by targeting ferroptosis pathway, and AKT1 may be a molecular marker of susceptibility to ferroptosis.

Our study reveals that piperine analog-2 (pip2) shows highest binding affinity (- 6.0 kcal/mol) by forming 6 hydrogen bonds with more hydrophobic interactions compared to other four analogs and standards. In conclusion, the piperine analog pip2, which shows strong inhibition affect in Akt1-cancer pathway, may be employed as chemotherapeutic drugs.

In conclusion, α-hederin augmented the chemotherapeutic potential of cisplatin against ESTs; this effect was at least partly mediated through suppressing the chemokine SDF1/CXCR4/p-AKT/NFκB signaling. Further studies are recommended to verify the chemotherapeutic potential of α-hederin in other breast cancer models.

Through the network pharmacological analysis, six chemicals (quercetin, 4'-hydroxywogonin, sinensetin, 5, 7, 8, 3', 4'-pentamethoxyflavanone, 8-gingerdione and quercetin) were identified as the active ingredients, and five LZXP targets (AKT1, CYP1B1, PTGS2, MMP9, and EGFR) were found to be the crucial molecules in the treatment of GPL. This study provides a systematic and applicable method for the rapid screening and identification of the chemical constituents from LZXP, and an effective understanding the mechanism of LZXP in the treatment of GPL.

ATRi (ceralasertib) and AKTi (capivasertib) were used for further mechanistic studies. Our data suggest ATRi and AKTi combination could be a new therapeutic combination in HGSC with PARPi resistance. Mechanistically, our data reveal a previously unknown direct role of AKT1 and its interaction with DHX9 in R-loop resolution besides ATR.

We showed that PI3K/Akt1 pathway plays an important role in the sensitization of cancer cell lines with compromised function of ARID1A to PARPi treatment. We believe that using of PARPi monotherapy or in combination with radiation therapy is an appealing strategy for treating ARID1A-mutated cancers, as well as many other types of PI3K/Akt1-driven cancers.

On the one hand, our study demonstrates that Scutellaria baicalensis has the characteristics of multicomponent and multitarget synergistic effects in the treatment of breast cancer. On the other hand, we suggest that the best effective compound is coptisine targeting AKT1, which can provide a theoretical basis for the further study of the drug-like active compounds and offer molecular mechanisms behind their roles in the treatment of breast cancer.

Both 3-hydroxyflavone and luteolin were demonstrated to induce apoptosis and inhibit the proliferation of HepG2 cells. Our study provides scientific evidence supporting the use of CTFs for the treatment of liver cancer.

Data indicates that aPKCs upregulate Akt1/NF-κB and TGF-β pathways in NB cells through an association with 14-3-3 and Smad2/3 that can be diminished by aPKC inhibitors. In summary, both inhibitors appear to be promising potential neuroblastoma therapeutics and merit further research.

The molecular docking results revealed that 7-O-galloyltricetiflavan and 7,4'-di-O-galloyltricetiflavan (P16/P20) can bind to α-amylase and α-glucosidase pockets with binding energies lower than -6 kcal/mol. Our study provides guidance for the development of antibacterial and antidiabetic products based on A. clypearia and can be used as a reference for the evaluation of bioactivity of other herbs.