Aurora kinase A regulates liver regeneration through macrophages polarization and Wnt/ß-catenin signalling.

BACKGROUND AND AIMS: Liver regeneration is a complex process regulated by a variety of cells, cytokines and biological pathways. Aurora kinase A (AURKA) is a serine/threonine kinase that plays a role in centrosome maturation and spindle formation during the cell division cycle. The purpose of this study was to further explore the mechanism of AURKA on liver regeneration and to identify new possible targets for liver regeneration. METHODS: The effect and mechanism of AURKA on liver regeneration were studied using a 70% hepatectomy model. Human liver organoids were used as an in vitro model to investigate the effect of AURKA on hepatocyte proliferation. RESULTS: AURKA inhibition significantly reduced the level of ß-catenin protein by reducing the phosphorylation level of glycogen synthase kinase-3ß (GSK-3ß), leading to the inhibition of liver regeneration. Further studies showed that AURKA co-localized and interacted with GSK-3ß in the cytoplasm of hepatocytes. When phosphorylation of GSK-3ß was enhanced, the total GSK-3ß level remained unchanged, while AURKA was not affected, and ß-catenin protein levels were increased. In addition, AURKA inhibition affected the formation and proliferation of human liver organoids. Furthermore, AURKA inhibition led to the polarization of M1 macrophages and the release of interleukin-6 and Tumour necrosis factor α, which also led to reduced liver regeneration and increased liver injury. CONCLUSIONS: These results provide more details on the mechanism of liver regeneration and suggest that AURKA is an important regulator of this mechanism.

The Akt/GSK3ß/ß-catenin signaling regulated by ZCCHC14 is responsible for accelerating the proliferation of hepatocellular carcinoma.

PURPOSE: To clarify how ZCCHC14 affects the development of hepatocellular carcinoma (HCC). METHODS: Differential levels of ZCCHC14 in HCC tissues and cells were examined. Proliferative and migratory changes in HCC cells with overexpression or knockdown of ZCCHC14 were detected using 5-Ethynyl-2'- deoxyuridine (EdU) and Transwell assay, respectively. Expression changes of p-Akt/Akt, p-GSK3ß/GSK3ß and ß-catenin in HCC cells mediated by ZCCHC14 were determined. Intervened by the p-Akt activator SC79 or overexpression of ß-catenin, further validated the involvement of the Akt/GSK3ß/ß-catenin signaling in HCC cell phenotypes mediated by ZCCHC14. RESULTS: Upregulated ZCCHC14 in HCC accelerated in vitro proliferative potential of HCC cells. Knockdown of ZCCHC14 inactivated the Akt/GSK3ß/ß-catenin signaling and inhibited malignant phenotypes of HCC, which were partially reversed by SC79 induction or overexpression of ß-catenin. CONCLUSIONS: By activating the Akt/GSK3ß/ß-catenin signaling, ZCCHC14 accelerates HCC cells proliferation.

CHIR99021, trough GSK-3ß Targeting, Reduces Epithelioid Sarcoma Cell Proliferation by Activating Mitotic Catastrophe and Autophagy.

Epithelioid sarcoma (ES) is a rare disease representing <1% of soft tissue sarcomas. Current therapies are based on anthracycline alone or in combination with ifosfamide or other cytotoxic drugs. ES is still characterized by a poor prognosis with high rates of recurrence. Indeed, for years, ES survival rates have remained stagnant, suggesting that conventional treatments should be revised and improved. New therapeutic approaches are focused to target the key regulators of signaling pathways, the causative markers of tumor pathophysiology. To this end, we selected, among the drugs to which an ES cell line is highly sensitive, those that target signaling pathways known to be dysregulated in ES. In particular, we found a key role for GSK-3ß, which results in up-regulation in tumor versus normal tissue samples and associated to poor prognosis in sarcoma patients. Following this evidence, we evaluated CHIR99021, a GSK-3 inhibitor, as a potential drug for use in ES therapy. Our data highlight that, in ES cells, CHIR99021 induces cell cycle arrest, mitotic catastrophe (MC) and autophagic response, resulting in reduced cell proliferation. Our results support the potential efficacy of CHIR99021 in ES treatment and encourage further preclinical and clinical studies.

Tideglusib, a Non-ATP Competitive Inhibitor of GSK-3ß as a Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is the most common degenerative motor neuron disease in adults. About 97% of ALS patients present TDP-43 aggregates with post-translational modifications, such as hyperphosphorylation, in the cytoplasm of affected cells. GSK-3ß is one of the protein kinases involved in TDP-43 phosphorylation. Up-regulation of its expression and activity is reported on spinal cord and cortex tissues of ALS patients. Here, we propose the repurposing of Tideglusib, an in-house non-ATP competitive GSK-3ß inhibitor that is currently in clinical trials for autism and myotonic dystrophy, as a promising therapeutic strategy for ALS. With this aim we have evaluated the efficacy of Tideglusib in different experimental ALS models both in vitro and in vivo. Moreover, we observed that GSK-3ß activity is increased in lymphoblasts from sporadic ALS patients, with a simultaneous increase in TDP-43 phosphorylation and cytosolic TDP-43 accumulation. Treatment with Tideglusib decreased not only phospho-TDP-43 levels but also recovered its nuclear localization in ALS lymphoblasts and in a human TDP-43 neuroblastoma model. Additionally, we found that chronic oral treatment with Tideglusib is able to reduce the increased TDP-43 phosphorylation in the spinal cord of Prp-hTDP-43A315T mouse model. Therefore, we consider Tideglusib as a promising drug candidate for ALS, being proposed to start a clinical trial phase II by the end of the year.

Keratin 19 interacts with GSK3ß to regulate its nuclear accumulation and degradation of cyclin D3.

Cyclin D3 regulates the G1/S transition and is frequently overexpressed in several cancer types including breast cancer, where it promotes tumor progression. Here we show that a cytoskeletal protein keratin 19 (K19) physically interacts with a serine/threonine kinase GSK3ß and prevents GSK3ß-dependent degradation of cyclin D3. The absence of K19 allowed active GSK3ß to accumulate in the nucleus and degrade cyclin D3. Specifically, the head (H) domain of K19 was required to sustain inhibitory phosphorylation of GSK3ß Ser9, prevent nuclear accumulation of GSK3ß, and maintain cyclin D3 levels and cell proliferation. K19 was found to interact with GSK3ß and K19-GSK3ß interaction was mapped out to require Ser10 and Ser35 residues on the H domain of K19. Unlike wildtype K19, S10A and S35A mutants failed to maintain total and nuclear cyclin D3 levels and induce cell proliferation. Finally, we show that the K19-GSK3ß-cyclin D3 pathway affected sensitivity of cells toward inhibitors to cyclin-dependent kinase 4 and 6 (CDK4/6). Overall, these findings establish a role for K19 in the regulation of GSK3ß-cyclin D3 pathway and demonstrate a potential strategy for overcoming resistance to CDK4/6 inhibitors.

Investigating function of long noncoding RNA of HOTAIRM1 in progression of SKOV3 ovarian cancer cells.

Ovarian cancer is one of the most heterogeneous malignancies in the field of gynecologic oncology. Deregulation of long noncoding RNAs (lncRNAs) is implicated in carcinogenesis. Therefore, the present study was conducted to investigate the possible role of lncRNA of HOXA transcript antisense intergenic RNA myeloid-specific 1(HOTAIRM1) in progression of SKOV3 cells in ovarian cancer and also its underlying molecular mechanisms. HOTAIRM1 expression level will be measured by real-time polymerase chain reaction (PCR) in SKOV3 cells. For determining the effect of HOTAIRM1 silencing on progression of SKOV3 cells, siHOTAIRM1 will be designed and transfected into cells using a liposomal approach. MTT and trypan blue assays will be used to determine the effect of HOTAIRM1 silencing on cell proliferation. Apoptosis of the cells will be detected by flow cytometry. Furthermore, expressions of apoptosis-related genes and Wnt pathway-related proteins and genes will be analyzed by Western blot and real-time PCR. HOTAIRM1 was overexpressed in SKOV3 cells. Silencing of HOTAIRM1 alleviated cell proliferation, and increased cell apoptosis of SKOV3 cells. Moreover, siHOTAIRM1 significantly increased expression of pro-apoptotic agents, such as Bad and Bax, while it decreased expressions of Bid and Bcl-2 (anti-apoptotic agents). Also, silencing of HOTAIRM1 resulted in a suppressed expression of Wnt pathway-related proteins and also expression of its downstream target gene, matrix metalloproteinase 9(MMP9). Our findings provided new insights into function of lncRNA of HOTAIRM1 in progression of ovarian cancer by modulating Wnt pathway and its downstream target gene, MMP9.

GSK3ß-Mediated Expression of CUG-Translated WT1 Is Critical for Tumor Progression.

The Wilms' tumor 1 (WT1) gene is well known as a chameleon gene. It plays a role as a tumor suppressor in Wilms' tumor but also acts as an oncogene in other cancers. Previously, our group reported that a canonical AUG starting site for the WT1 protein (augWT1) acts as a tumor suppressor, whereas a CUG starting site for the WT1 protein (cugWT1) functions as an oncogene. In this study, we report an oncogenic role of cugWT1 in the AOM/DSS-induced colon cancer mouse model and in a urethane-induced lung cancer model in mice lacking cugWT1. Development of chemically-induced tumors was significantly depressed in cugWT1-deficient mice. Moreover, glycogen synthase kinase 3ß promoted phosphorylation of cugWT1 at S64, resulting in ubiquitination and degradation of the cugWT1 associated with the F-box-/- WD repeat-containing protein 8. Overall, our findings suggest that inhibition of cugWT1 expression provides a potential candidate target for therapy. SIGNIFICANCE: These findings demonstrate that CUG-translated WT1 plays an oncogenic role in vivo, and GSK3ß-mediated phosphorylation of cugWT1 induces its ubiquitination and degradation in concert with FBXW8.

Glycogen Synthase Kinase 3ß Promotes Postoperative Cognitive Dysfunction by Inducing the M1 Polarization and Migration of Microglia.

Postoperative cognitive dysfunction (POCD) is a common postoperative central nervous system complication, especially in the elderly. It has been consistently reported that the pathological process of this clinical syndrome is related to neuroinflammation and microglial proliferation. Glycogen synthase kinase 3ß (GSK-3ß) is a widely expressed kinase with distinct functions in different types of cells. The role of GSK-3ß in regulating innate immune activation has been well documented, but as far as we know, its role in POCD has not been fully elucidated. Lithium chloride (LiCl) is a widely used inhibitor of GSK-3ß, and it is also the main drug for the treatment of bipolar disorder. Prophylactic administration of lithium chloride (2 mM/kg) can inhibit the expression of proinflammatory mediators in the hippocampus, reduce the hippocampal expression of NF-κB, and increase both the downregulation of M1 microglial-related genes (inducible nitric oxide synthase and CD86) and upregulation of M2 microglial-related genes (IL-10 and CD206), to alleviate the cognitive impairment caused by orthopedic surgery. In vitro, LiCl reversed LPS-induced production of proinflammatory mediators and M1 polarization of microglia. To sum up these results, GSK-3ß is a key contributor to POCD and a potential target of neuroprotective strategies.

RPN2 is targeted by miR-181c and mediates glioma progression and temozolomide sensitivity via the wnt/ß-catenin signaling pathway.

Accumulating evidence indicates that the dysregulation of the miRNAs/mRNA-mediated carcinogenic signaling pathway network is intimately involved in glioma initiation and progression. In the present study, by performing experiments and bioinformatics analysis, we found that RPN2 was markedly elevated in glioma specimens compared with normal controls, and its upregulation was significantly linked to WHO grade and poor prognosis. Knockdown of RPN2 inhibited tumor proliferation and invasion, promoted apoptosis, and enhanced temozolomide (TMZ) sensitivity in vitro and in vivo. Mechanistic investigation revealed that RPN2 deletion repressed ß-catenin/Tcf-4 transcription activity partly through functional activation of glycogen synthase kinase-3ß (GSK-3ß). Furthermore, we showed that RPN2 is a direct functional target of miR-181c. Ectopic miR-181c expression suppressed ß-catenin/Tcf-4 activity, while restoration of RPN2 partly reversed this inhibitory effect mediated by miR-181c, implying a molecular mechanism in which TMZ sensitivity is mediated by miR-181c. Taken together, our data revealed a new miR-181c/RPN2/wnt/ß-catenin signaling axis that plays significant roles in glioma tumorigenesis and TMZ resistance, and it represents a potential therapeutic target, especially in GBM.

Glycogen synthase kinase-3ß participates in acquired resistance to gemcitabine in pancreatic cancer.

Acquisition of resistance to gemcitabine is a challenging clinical and biological hallmark property of refractory pancreatic cancer. Here, we investigated whether glycogen synthase kinase (GSK)-3ß, an emerging therapeutic target in various cancer types, is mechanistically involved in acquired resistance to gemcitabine in human pancreatic cancer. This study included 3 gemcitabine-sensitive BxPC-3 cell-derived clones (BxG30, BxG140, BxG400) that acquired stepwise resistance to gemcitabine and overexpressed ribonucleotide reductase (RR)M1. Treatment with GSK3ß-specific inhibitor alone attenuated the viability and proliferation of the gemcitabine-resistant clones, while synergistically enhancing the efficacy of gemcitabine against these clones and their xenograft tumors in rodents. The gemcitabine-resensitizing effect of GSK3ß inhibition was associated with decreased expression of RRM1, reduced phosphorylation of Rb protein, and restored binding of Rb to the E2 transcription factor (E2F)1. This was followed by decreased E2F1 transcriptional activity, which ultimately suppressed the expression of E2F1 transcriptional targets including RRM1, CCND1 encoding cyclin D1, thymidylate synthase, and thymidine kinase 1. These results suggested that GSK3ß participates in the acquisition of gemcitabine resistance by pancreatic cancer cells via impairment of the functional interaction between Rb tumor suppressor protein and E2F1 pro-oncogenic transcription factor, thereby highlighting GSK3ß as a promising target in refractory pancreatic cancer. By providing insight into the molecular mechanism of gemcitabine resistance, this study identified a potentially novel strategy for pancreatic cancer chemotherapy.

Suppression of G6PD induces the expression and bisecting GlcNAc-branched N-glycosylation of E-Cadherin to block epithelial-mesenchymal transition and lymphatic metastasis.

BACKGROUND: As the rate-limit enzyme of the pentose phosphate pathway, glucose-6-phosphate dehydrogenase (G6PD) plays important roles in tumour progression, but the exact mechanism through which G6PD controls cancer metastasis remains unclear. METHODS: G6PD expression in resected oral squamous cell carcinoma (OSCC) samples was analysed by immunohistochemistry. The effects and mechanism of G6PD suppression on OSCC cell lines were measured by transwell assay, wound healing assay, western and lectin blot, mass spectrometer analysis, ChIP-PCR, and luciferase reporter assay. BALB/c-nude mice were used to establish orthotopic xenograft model. RESULTS: G6PD expression in the tumours of 105 OSCC patients was associated with lymphatic metastasis and prognosis. In vitro cellular study suggested that G6PD suppression impaired cell migration, invasion, and epithelial-mesenchymal transition. Furtherly, G6PD knockdown activated the JNK pathway, which then blocked the AKT/GSK-3ß/Snail axis to induce E-Cadherin expression and transcriptionally regulated MGAT3 expression to promote bisecting GlcNAc-branched N-glycosylation of E-Cadherin. An orthotopic xenograft model further confirmed that dehydroepiandrosterone reduced lymphatic metastatic rate of OSCC, which was partially reversed by JNK inhibition. CONCLUSIONS: Suppression of G6PD promoted the expression and bisecting GlcNAc-branched N-glycosylation of E-Cadherin via activating the JNK pathway, which thus acted on OSCC metastasis.

Glycogen synthase kinase-3ß promotes radiation-induced lung fibrosis by regulating ß-catenin/lin28 signaling network to determine type II alveolar stem cell transdifferentiation state.

The role of type II alveolar epithelial stem cells (AEC II) for alveolar repair in radiation-induced lung fibrosis (RILF) remains largely unknown, mainly because of AEC II phenotype's spontaneous change in vitro. Cell differentiation status is determined by Lin28 and let-7 miRNAs in see-saw-pattern. Lin28, a repressor of let-7 and a stem cell marker, is activated by ß-catenin. The expression of ß-catenin is regulated by GSK-3ß/TGF-ß1 signaling. To understand the true role of AEC II in RILF, we freshly isolated primary AEC II directly from thoracically irradiated lungs. We then explored the expressions of cell phenotype markers and differentiation regulators in these isolated AEC II to analyze the correlation between GSK-3ß/TGF-ß1/ß-catenin signaling pathway, lin28/let-7 balance, and AEC II phenotypes at different injury phases following irradiation. Results showed that isolated single primary cells displayed AEC II ultrastructural features and proSP-C positive. The gene expressions of prosp-c (an AEC II biomarker) and hopx (an AEC I marker) significantly increased in isolated AEC II during injury repair phase (P < .001 and P < .05) but decreased at end-stage of injury, while mesenchymal markers increased in both isolated AEC II and irradiated lungs. mRNA levels of gsk-3ß, tgf-ß1, and ß-catenin increased in all irradiated AEC II, but more pronounced in the second half of injury phase (P < .05-P < .001). Similarly, the expression of lin28 was also significantly elevated in isolated AEC II at the late phase (P < .05-P < .001). Four let-7 miRNAs were significantly upregulated in all irradiated AEC II groups (P < .05-P < .001). The time-dependent and highly consistent uptrends for four lin28/let-7 ratios in sorted AEC II contrasted to downtrends in irradiated lungs. In conclusion, RILF occurred when GSK-3ß/TGF-ß1 signaling increased ß-catenin levels, which led to the augmentation of AEC II population by elevated lin28/let-7 ratio and the transcription of profibrotic cytokines and factors, thereby inducing AEC II to undergo transdifferentiation into mesenchymal cells.

Toxoplasma gondii Chinese I genotype Wh6 strain infection induces tau phosphorylation via activating GSK3ß and causes hippocampal neuron apoptosis.

Toxoplasma gondii (T. gondii) is a neurophilic and intracellular parasite that can affect plenty of vertebrate animals, including humans. Recent researches indicate that T. gondii infection is associated with neurodegenerative diseases such as Alzheimer's disease(AD). In addition, tau hyper-phosphorylation is a crucial event leading to the formation of nerve fiber tangles in AD. Despite the efforts to understand the interactions between T. gondii and AD, there are no clear results available so far. Here, we infected mice with the T. gondii of the Chinese 1 genotype Wh6 strain (TgCtwh6) for 60 days. Then we observed the formation of tissue cysts in the brain, the damage of neuron and the increased expression of phosphorylated tau (p-tau) in the hippocampal tissue of the mice. Similarly, we also found that p-tau, glycogen synthase kinase 3 beta (GSK3ß), and phosphorylated GSK3ß (p-GSK3ß) were upregulated in vitro in TgCtwh6 challenged hippocampal neuron cell strain, HT22 cells. We noted a down-regulated expression of GSK3ß,p-GSK3ß, and p-tau in HT22 cells, which were pretreated with LiCl, an inhibitor of GSK3ß. These data suggested that p-GSK3ß may mediate tau phosphorylation after TgCtwh6 infection. Furthermore, TgCtwh6 infection also caused the increased expression of Bax and Caspase3, the decreased expression of Bcl-XL in HT22 cells, which had both early and late apoptosis. In all, our results indicated that TgCtwh6 infection not only led to phosphorylation of tau via activating GSK3ß but also promoted hippocampal neuron apoptosis. Our research may partially reveal the mechanism with which TgCtwh6 induce neurofibrillary pathology.

O-GlcNAc impairs endothelial function in uterine arteries from virgin but not pregnant rats: The role of GSK3ß.

Increased O-Linked ß-N-acetylglucosamine (O-GlcNAc) is observed in several pathologies, and unbalanced O-GlcNAcylation levels favor endothelial dysfunction. Whether augmented O-GlcNAc impacts the uterine artery (UA) function and how it affects the UA during pregnancy remains to be elucidated. We hypothesized that glucosamine treatment increases O-GlcNAc, leading to uterine artery dysfunction and this effect is prevented by pregnancy. Pregnant (P) and non-pregnant (NP) Wistar rats were treated with glucosamine (300 mg/kg; i.p.) for 21 days. Concentration response-curves (CRC) to acetylcholine (in the presence or absence of L-NAME) and sodium nitroprusside were performed in UAs. In NP rats, glucosamine treatment increased O-GlcNAc expression in UAs accompanied by decreased endothelium-dependent relaxation, which was abolished by L-NAME. Endothelial nitric oxide synthase (eNOS) activity and total Akt expression were decreased by glucosamine-treatment in NP rats. Further, NP rats treated with glucosamine displayed increased glycogen synthase kinase 3 beta (GSK3ß) activation and O-GlcNAc-transferase (OGT) expression in the UA. P rats treated with glucosamine displayed decreased O-GlcNAc in UAs and it was accompanied by improved relaxation to acetylcholine, whereas eNOS and GSK3ß activity and total Akt and OGT expression were unchanged. Sodium nitroprusside-induced relaxation was not changed in all groups, indicating that glucosamine treatment led to endothelial dysfunction in NP rats. The underlying mechanism is, at least in part, dependent on Akt/GSK3ß/OGT modulation. We speculate that during pregnancy, hormonal alterations play a protective role in preventing O-GlcNAcylation-induced endothelial dysfunction in the UAs.

Alpinia oxyphylla-Schisandra chinensis Herb Pair Alleviates Amyloid-ß Induced Cognitive Deficits via PI3K/Akt/Gsk-3ß/CREB Pathway.

Alzheimer's disease (AD), one of the most common neurodegenerative diseases, threatens people's health. Based on the theory of traditional Chinese medicine (TCM) efficacy and treatment theory, we first proposed the Alpinia oxyphylla-Schisandra chinensis herb pair (ASHP) for finding a candidate of AD treatment. This study aimed at exploring the effects of ASHP on improving the cognitive function and neurodegeneration, and revealing the possible mechanism. In this study, an amyloid-ß (Aß) induced AD model was established in mice via intracerebroventricular injection. The Y-maze test and Morris water maze test were carried out to observe the behavioral change of mice, which showed that ASHP significantly ameliorated cognitive impairment. In addition, ASHP reduced amyloid-ß deposition and downregulated the hyperphosphorylation of tau via immunofluorescence assay and western blot analysis, respectively. Subsequently we focused on the PI3K/Akt pathway that is a classical pathway related to nervous system diseases. It also noticeably ASHP improved the histopathological changes in the hippocampus and cortex. Moreover, it was found that ASHP could upregulate the PI3K/Akt/Gsk-3ß/CREB signaling pathway in N2a-SwedAPP cells. Taken together, it suggests that ASHP might reverse cognitive deficits and neurodegeneration via PI3K/Akt/Gsk-3ß/CREB pathway.

The Roles of GSK-3ß in Regulation of Retinoid Signaling and Sorafenib Treatment Response in Hepatocellular Carcinoma.

Rationale: Glycogen synthase kinase-3ß (GSK-3ß) plays key roles in metabolism and many cellular processes. It was recently demonstrated that overexpression of GSK-3ß can confer tumor growth. However, the expression and function of GSK-3ß in hepatocellular carcinoma (HCC) remain largely unexplored. This study is aimed at investigating the role and therapeutic target value of GSK-3ß in HCC. Methods: We firstly clarified the expression of GSK-3ß in human HCC samples. Given that deviated retinoid signalling is critical for HCC development, we studied whether GSK-3ß could be involved in the regulation. Since sorafenib is currently used to treat HCC, the involvement of GSK-3ß in sorafenib treatment response was determined. Co-immunoprecipitation, GST pull down, in vitro kinase assay, luciferase reporter and chromatin immunoprecipitation were used to explore the molecular mechanism. The biological readouts were examined with MTT, flow cytometry and animal experiments. Results: We demonstrated that GSK-3ß is highly expressed in HCC and associated with shorter overall survival (OS). Overexpression of GSK-3ß confers HCC cell colony formation and xenograft tumor growth. Tumor-associated GSK-3ß is correlated with reduced expression of retinoic acid receptor-ß (RARß), which is caused by GSK-3ß-mediated phosphorylation and heterodimerization abrogation of retinoid X receptor (RXRα) with RARα on RARß promoter. Overexpression of functional GSK-3ß impairs retinoid response and represses sorafenib anti-HCC effect. Inactivation of GSK-3ß by tideglusib can potentiate 9-cis-RA enhancement of sorafenib sensitivity (tumor inhibition from 48.3% to 93.4%). Efficient induction of RARß by tideglusib/9-cis-RA is required for enhanced therapeutic outcome of sorafenib, which effect is greatly inhibited by knocking down RARß. Conclusions: Our findings demonstrate that GSK-3ß is a disruptor of retinoid signalling and a new resistant factor of sorafenib in HCC. Targeting GSK-3ß may be a promising strategy for HCC treatment in clinic.

Neuronal Protein Tyrosine Phosphatase 1B Hastens Amyloid ß-Associated Alzheimer's Disease in Mice.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, resulting in the progressive decline of cognitive function in patients. Familial forms of AD are tied to mutations in the amyloid precursor protein, but the cellular mechanisms that cause AD remain unclear. Inflammation and amyloidosis from amyloid ß (Aß) aggregates are implicated in neuron loss and cognitive decline. Inflammation activates the protein-tyrosine phosphatase 1B (PTP1B), and this could suppress many signaling pathways that activate glycogen synthase kinase 3ß (GSK3ß) implicated in neurodegeneration. However, the significance of PTP1B in AD pathology remains unclear. Here, we show that pharmacological inhibition of PTP1B with trodusquemine or selective ablation of PTP1B in neurons prevents hippocampal neuron loss and spatial memory deficits in a transgenic AD mouse model with Aß pathology (hAPP-J20 mice of both sexes). Intriguingly, while systemic inhibition of PTP1B reduced inflammation in the hippocampus, neuronal PTP1B ablation did not. These results dissociate inflammation from neuronal loss and cognitive decline and demonstrate that neuronal PTP1B hastens neurodegeneration and cognitive decline in this model of AD. The protective effect of PTP1B inhibition or ablation coincides with the restoration of GSK3ß inhibition. Neuronal ablation of PTP1B did not affect cerebral amyloid levels or plaque numbers, but reduced Aß plaque size in the hippocampus. In summary, our preclinical study suggests that targeting PTP1B may be a new strategy to intervene in the progression of AD.SIGNIFICANCE STATEMENT Familial forms of Alzheimer's disease (AD) are tied to mutations in the amyloid precursor protein, but the cellular mechanisms that cause AD remain unclear. Here, we used a mouse model expressing human amyloid precursor protein bearing two familial mutations and asked whether activation of a phosphatase PTP1B participates in the disease process. Systemic inhibition of this phosphatase using a selective inhibitor prevented cognitive decline, neuron loss in the hippocampus, and attenuated inflammation. Importantly, neuron-targeted ablation of PTP1B also prevented cognitive decline and neuron loss but did not reduce inflammation. Therefore, neuronal loss rather than inflammation was critical for AD progression in this mouse model, and that disease progression could be ameliorated by inhibition of PTP1B.

Inhibition of GSK-3ß activity suppresses HCC malignant phenotype by inhibiting glycolysis via activating AMPK/mTOR signaling.

Glycogen synthase kinase-3 beta (GSK-3ß) has been shown to play a critical role in the development of many cancers, but its role in hepatocellular carcinoma (HCC) remains unclear. Deregulating cellular energetics is a signature hallmark of cancer, therefore modulating cancer metabolism has become an attractive anti-cancer approach in recent years. As a key enzyme in glucose metabolism, understanding the role of GSK-3ß in cancer metabolic process may facilitate the development of effective therapeutic approach for HCC. In this study, we showed that inhibition of GSK-3ß led to diminished viability, metastasis and tumorigenicity in HCC cells. Suppression of GSK-3ß activity also reduced glucose consumption, lactate production and adenosine triphosphate (ATP) levels in HCC cells. The decreased extracellular acidification rate (ECAR) and down-regulated key enzymes on the glycolysis pathway by GSK3ß inhibition demonstrated that GSK-3ß was involved in glycolysis process of HCC. Mechanistically, the metabolic change and anti-cancer effect by GSK-3ß inhibition was achieved mainly through activation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling, which negatively affected glycolysis and cell proliferation. The results from primary HCC cells and from in vivo nude mice model confirmed our observations. Our study results indicated that GSK-3ß may become a promising therapeutic target for HCC.

High lithium levels in tobacco may account for reduced incidences of both Parkinson's disease and melanoma in smokers through enhanced ß-catenin-mediated activity.

Parkinson's disease (PD) patients have higher rates of melanoma and vice versa, observations suggesting that the two conditions may share common pathogenic pathways. ß-Catenin is a transcriptional cofactor that, when concentrated in the nucleus, upregulates the expression of canonical Wnt target genes, such as Nurr1, many of which are important for neuronal survival. ß-Catenin-mediated activity is decreased in sporadic PD as well as in leucine-rich repeat kinase 2 (LRRK2) and ß-glucosidase (GBA) mutation cellular models of PD, which is the most common genetic cause of and risk for PD, respectively. In addition, ß-catenin expression is significantly decreased in more aggressive and metastatic melanoma. Multiple observational studies have shown smokers to have significantly lower rates of PD as well as melanoma implying that tobacco may contain one or more elements that protect against both conditions. In support, smoker's brains have significantly reduced levels of α-synuclein, a pathological intracellular protein found in PD brain and melanoma cells. Tobacco contains very high lithium levels compared to other plants. Lithium has a broad array of neuroprotective actions, including enhancing autophagy and reducing intracellular α-synuclein levels, and is effective in both neurotoxin and transgenic preclinical PD models. One of lithium's neuroprotective actions is enhancement of ß-catenin-mediated activity leading to increased Nurr1 expression through its ability to inhibit glycogen synthase kinase-3 ß (GSK-3ß). Lithium also has anti-proliferative effects on melanoma cells and the clinical use of lithium is associated with a reduced incidence of melanoma as well as reduced melanoma-associated mortality. This is the first known report hypothesizing that inhaled lithium from smoking may account for the associated reduced rates of both PD and melanoma and that this protection may be mediated, in part, through lithium-induced GSK-3ß inhibition and consequent enhanced ß-catenin-mediated activity. This hypothesis could be directly tested in clinical trials assessing lithium therapy's ability to affect ß-catenin-mediated activity and slow disease progression in patients with PD or melanoma.

No evidence so far of a major role of AKT1 and GSK3B in the pathogenesis of antipsychotic-induced tardive dyskinesia.

OBJECTIVE: AKT1 and GSK3B take part in one of the intracellular cascades activated by the D2 dopamine receptor (DRD2). This receptor is antagonized by antipsychotics and plays a role in the pathogenesis of antipsychotic-induced tardive dyskinesia (TD). The present study investigated association of several polymorphisms in the two candidate genes, AKT1 and GSK3B, with TD in antipsychotic-treated patients with schizophrenia. METHODS: DNA samples from 449 patients from several Siberian regions (Russia) were genotyped, and the results were analyzed using chi-squared tests and analyses of variance. RESULTS: Antipsychotic-induced TD was not associated with either of the tested functional polymorphisms (rs334558, rs1130214, and rs3730358). CONCLUSIONS: Despite regulation of AKT1 and GSK3B by DRD2, we found no evidence that these two kinases play a major role in the pathogenesis of antipsychotic-induced TD. These results agree with previously published data and necessitate further exploration of other pathogenic mechanisms, such as neurotoxicity due to excessive dopamine metabolism.