• Asian Pacific Journal of Cancer Prevention
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• v.15 no.23
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• pp.10463-10468
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• 2015

Opisthorchis viverrini (Ov) infection is the major etiological factor for cholangiocarcinoma (CCA), especially in northeast Thailand. We have previously reported significant involvement of PI3K/AKT/PTEN and $Wnt/{\beta}$-catenin in human CCA tissues. The present study, therefore, examined the expression and activation of PI3K/AKT/PTEN and $Wnt/{\beta}$-catenin signaling components during Ov-induced cholangiocarcinogenesis in a hamster animal model. Hamsters were divided into two groups; non-treated and Ov plus NDMA treated. The results of immunohistochemical staining showed an upregulation of PI3K/AKT signaling as determined by elevated expression of the $p85{\alpha}$-regulatory and $p110{\alpha}$-catalytic subunits of PI3K as well as increased expression and activation of AKT during cholangiocarcinogenesis. Interestingly, the staining intensity of activated AKT (p-AKT) increased in the apical regions of the bile ducts and strong staining was detected where the liver fluke resides. Moreover, PTEN, a negative regulator of PI3K/AKT, was suppressed by decreased expression and increased phosphorylation during cholangiocarcinogenesis. We also detected upregulation of $Wnt/{\beta}$-catenin signaling as determined by increased positive staining of Wnt3, Wnt3a, Wnt5a, Wnt7b and ${\beta}$-catenin, corresponded with the period of cholangiocarcinogenesis. Furthermore, nuclear staining of ${\beta}$-catenin was observed in CCA tissues. Our results suggest the liver fluke infection causes chronic inflammatory conditions which lead to upregulation of the PI3K/AKT and $Wnt/{\beta}$-catenin signaling pathways which may drive CCA carcinogenesis. These results provide useful information for drug development, prevention and treatment of CCA.

• Molecules and Cells
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• v.38 no.6
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• pp.535-539
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• 2015

Olfactory stimulation activates multiple signaling cascades in order to mediate activity-driven changes in gene expression that promote neuronal survival. To date, the mechanisms involved in activity-dependent olfactory neuronal survival have yet to be fully elucidated. In the current study, we observed that olfactory sensory stimulation, which caused neuronal activation, promoted activation of the phosphatidylinositol 3'-kinase (PI3K)/Akt pathway and the expression of Bcl-2, which were responsible for olfactory receptor neuron (ORN) survival. We demonstrated that Bcl-2 expression increased after odorant stimulation both in vivo and in vitro. We also showed that odorant stimulation activated Akt, and that Akt activation was completely blocked by incubation with both a PI3K inhibitor (LY294002) and Akt1 small interfering RNA. Moreover, blocking the PI3K/Akt pathway diminished the odorantinduced Bcl-2 expression, as well as the effects on odorant-induced ORN survival. A temporal difference was noted between the activation of Akt1 and the expression of Bcl-2 following odorant stimulation. Blocking the PI3K/Akt pathway did not affect ORN survival in the time range prior to the increase in Bcl-2 expression, implying that these two events, activation of the PI3K pathway and Bcl-2 induction, were tightly connected to promote post-translational ORN survival. Collectively, our results indicated that olfactory activity activated PI3K/Akt, induced Bcl-2, and promoted long term ORN survival as a result.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.4
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• pp.2201-2205
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• 2013

Colorectal cancer (CRC) is one of the most common cancers in many parts of the world. Its development is a multi-step process involving three distinct stages, initiation that alters the molecular message of a normal cell, followed by promotion and progression that ultimately generates a phenotypically altered transformed malignant cell. Reports have suggested an association of the phosphoinositide-3-kinase (PI3K)/Akt pathway with colon tumorigenesis. Activation of Akt signaling and impaired expression of phosphatase and tensin homolog (PTEN) (a negative regulator of Akt) has been reported in 60-70% of human colon cancers and inhibitors of PI3K/Akt signaling have been suggested as potential therapeutic agents. Around 80% of human colon tumors possess mutations in the APC gene and half of the remainder feature ${\beta}$-catenin gene mutations which affect downstream signaling of the PI3K/Akt pathway. In recent years, there has been a great focus in targeting these signaling pathways, with natural and synthetic drugs reducing the tumor burden in different experiment models. In this review we survey the role of PI3K/Akt/mTOR and Wnt signaling in CRC.

• Journal of Life Science
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• v.32 no.2
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• pp.86-93
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• 2022

Lupeol is a type of pentacyclic triterpene and has been reported to have pharmacological activities against various diseases; however, the effect of lupeol on glucose absorption has not been elucidated yet. This study aimed to investigate the effect of lupeol on glucose uptake in 3T3-L1 adipocytes. Lupeol significantly facilitated glucose uptake by translocating glucose transporter type 4 (GLUT4) to the plasma membrane of the 3T3-L1 adipocytes, which was related to activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and 5 'adenosine monophosphate-activated protein kinase (AMPK) pathways. In the PI3K/AKT pathway, lupeol stimulates the phosphorylation of insulin receptor substrate 1 (IRS-1), which activates PI3K. Its activation by lupeol promotes the phosphorylation of AKT, but not the atypical protein kinase C isoforms ζ and λ. Lupeol also promoted the phosphorylation of AMPK. The activation of AMPK increased the expressions of the plasma membrane GLUT4 and the intracellular glucose uptake. The increase in the glucose uptake by lupeol was suppressed by wortmannin (PI3K inhibitor) and compound C (AMPK inhibitor) in the 3T3-L1 adipocytes. The results indicate that lupeol can facilitate glucose uptake by increasing insulin sensitivity through the stimulation of the expression of plasma membrane glucose transporter type 4 via the PI3K/AKT and AMPK pathways in the 3T3-L1 adipocytes.

• Journal of the Korean Society of Food Science and Nutrition
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• v.45 no.6
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• pp.835-842
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• 2016

The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway plays a crucial role in cancer occurrence by promoting cell proliferation and inhibiting apoptosis. In the present study, we evaluated the effect of a PI3K inhibitor, LY294002, on the chemosensitivity of gastric cancer cells to cordycepin, a predominant functional component of the fungus Cordyceps militaris, in AGS human gastric cancer cells and investigated possible underlying cellular mechanisms. Our results revealed that cordycepin inhibited viability of AGS cells in a concentration-dependent manner and induced apoptosis, as determined by apoptotic cell morphologies and fluorescence-activated cell sorting analysis associated with attenuated activation of the PI3K/Akt signaling pathway. Treatment with cordycepin in combination with a subtoxic concentration of LY294002 enhanced cordycepin-induced cytotoxicity and apoptotic potentials in AGS cells. Sensitization of LY294002 to cordycepin-induced apoptosis was accompanied by activation of caspases (caspases-3, -8, and -9) and was concomitant with poly(ADP-ribose) polymerase cleavage. Moreover, LY294002 up-regulated pro-apoptotic Bax and enhanced truncation of Bid in cordycepin-treated AGS cells, which was connected with increased loss of mitochondrial membrane potential and release of cytochrome c from mitochondria to the cytosol. Taken together, these results indicate that inhibition of the PI3K/Akt signaling pathway could augment cordycepin-induced apoptosis in human gastric cancer cells by up-regulating caspase activity through mitochondrial dysfunction.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.7
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• pp.2645-2651
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• 2015

Background: The phosphatidylinositol 3'-kinase/Akt (PI3K/Akt) pathway is a key regulator for HER2-overexpressing breast cancer, but data about whether activation of PI3K/Akt is associated with poor prognosis and resistance to trastuzumab therapy is controversial. In this study we investigated predictive and prognostic significance of expression of p27, Akt, PTEN and PI3K, which are components of the PI3K/Akt signaling pathway, in HER2-positive metastatic breast cancer (MBC), retrospectively. Materials and Methods: Fifty-four HER2-positive MBC patients who had received first-line trastuzumab-based therapy were recruited for the study group. All of the patient's breast tissue samples were examined for p27 and Akt expression. In addition, twenty-five patients with sufficient amount of tumor tissue were also examined for PTEN and PI3K expression. p27, Akt, PTEN and PI3K were evaluated by immunohistochemistry and their relationship with patient demographic features, tumor characteristics, response to trastuzumab-based treatment and survival outcomes were analyzed. Results: p27, Akt, PTEN and PI3K were positive in 25.9%, 70.4%, 24% and 96% of the cases, respectively. Nomne were significantly associated with response to trastuzumab and time to progression (TTP). A trend toward statistical significance for longer overall survival (OS) was found for PTEN-positive patients (p=0.058); there was no significant relationship between the other immunohistochemical variables and OS. When we analyzed groups regarding co-expression, the PTEN-negative/Akt-negative group had a significantly lower objective response rate (ORR) (20% vs 80%, p=0.023) and the PTEN-negative/p27-negative and PTEN-negative/Akt-negative groups had significantly lower median OS compared to other patients (26.4 months vs 76.1 months, p=0.005 and 25.6 months vs 52.0 months, p=0.007, respectively). Conclusions: p27, Akt, PTEN and PI3K expression is not statistically significantly associated with ORR, TTP and OS, individually. However, the combined evaluation of p27, Akt and PTEN could be helpful to predict the response to trastuzumab-based therapy and prognosis in HER2-positive MBC.

• The Korean Journal of Physiology and Pharmacology
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• v.24 no.5
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• pp.423-431
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• 2020

This study aimed to evaluate the effect of curcumin on brain hypoxic-ischemic (HI) damage in neonatal rats and whether the phosphoinositide 3-kinase (PI3K)/Akt/vascular endothelial growth factor (VEGF) signaling pathway is involved. Brain HI damage models were established in neonatal rats, which received the following treatments: curcumin by intraperitoneal injection before injury, insulin-like growth factor 1 (IGF-1) by subcutaneous injection after injury, and VEGF by intracerebroventricular injection after injury. This was followed by neurological evaluation, hemodynamic measurements, histopathological assessment, TUNEL assay, flow cytometry, and western blotting to assess the expression of p-PI3K, PI3K, p-Akt, Akt, and VEGF. Compared with rats that underwent sham operation, rats with brain HI damage showed remarkably increased neurological deficits, reduced right blood flow volume, elevated blood viscosity and haematocrit, and aggravated cell damage and apoptosis; these injuries were significantly improved by curcumin pretreatment. Meanwhile, brain HI damage induced the overexpression of p-PI3K, p-Akt, and VEGF, while curcumin pretreatment inhibited the expression of these proteins. In addition, IGF-1 treatment rescued the curcumin-induced down-regulated expression of p-PI3K, p-Akt, and VEGF, and VEGF overexpression counteracted the inhibitory effect of curcumin on brain HI damage. Overall, pretreatment with curcumin protected against brain HI damage by targeting VEGF via the PI3K/Akt signaling pathway in neonatal rats.

• Molecules and Cells
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• v.41 no.6
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• pp.532-544
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• 2018

Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumors of the gastrointestinal (GI) tract. In order to investigate a new treatment fot GIST, we hypothesized the effect of miR-374b targeting PTEN gene-mediated PI3K/Akt signal transduction pathway on proliferation and apoptosis of human gastrointestinal stromal tumor (GIST) cells. We obtained GIST tissues and adjacent normal tissues from 143 patients with GIST to measure the levels of miR-374b, PTEN, PI3K, Akt, caspase9, Bax, MMP2, MMP9, ki67, PCNA, P53 and cyclinD1. Finally, cell viability, cell cycle and apoptosis were detected. According to the KFGG analysis of DEGs, PTEN was involved in a variety of signaling pathways and miRs were associated with cancer development. The results showed that MiR-374b was highly expressed, while PTEN was downregulated in the GIST tissues. The levels of miR-374b, PI3K, AKT and PTEN were related to tumor diameter and pathological stage. Additionally, miR-374b increased the mRNA and protein levels of PI3K, Akt, MMP2, MMP9, P53 and cyclinD1, suggesting that miR-374b activates PI3K/Akt signaling pathway in GIST-T1 cells. Moreover, MiR374b promoted cell viability, migration, invasion, and cell cycle entry, and inhibited apoptosis in GIST cells. Taken together, the results indicated that miR-374b promotes viability and inhibits apoptosis of human GIST cells by targeting PTEN gene through the PI3K/Akt signaling pathway. Thus, this study provides a new potential target for GIST treatment.

• Korean Journal of Pharmacognosy
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• v.53 no.2
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• pp.64-69
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• 2022

When blood vessels are damaged, a rapid hemostatic response should occur in order to lower blood loss and keep normal circulation, and platelet activation and aggregation are essential. Nevertheless, abnormal or excessive platelet aggregation can be a reason of cardiovascular diseases including thrombosis, atherosclerosis, and stroke. Therefore, the screening for a substance which can regulate platelet activation and suppress aggregation reaction is very important for treatment and prevention of cardiovascular diseases. Artemether is a methyl ether derivative of artemisinin, which is isolated from the antimalarial plant Artemisia annua, but research on platelet aggregation or its mechanisms is still insufficient. This study identified the effects of artemether on U46619-induced human platelet aggregation and their granule secretion (ATP and serotonin release). In addition, the effects of artemether on the phosphorylation of PI3K/Akt or MAPK, which are related to signal transduction in platelet aggregation, were studied. As the results, artemether significantly lowered PI3K/Akt and MAPK phosphorylation, which inhibited platelet aggregation through granule secretion (ATP and serotonin release) dose-dependently. Therefore, we suggest that artemether is an antiplatelet substance that regulates PI3K/Akt and MAPK pathway and is of value as a therapeutic and preventive agent for platelet-derived cardiovascular diseases.

• Korean Journal of Clinical Laboratory Science
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• v.49 no.2
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• pp.99-107
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• 2017

A species of Cordyceps, an ingredient in Chinese traditional medicine well-known for its major component, cordycepin (3'-deoxyadenosine), has been known to have antiplatelet effects; however, its effects on regulation of phosphoprotein have not been fully elucidated. In this study, we investigated how cordycepin regulates the phosphoprotein, including phosphatidylinositol 3-kinase (PI3K)/Akt and p38, to inhibit platelet aggregation, which are concerned with fibrinogen binding to glycoprotein IIb/IIIa (${\alpha}IIb/{\beta}_3$) and granule secretion in platelets. Our finding suggests that cordycepin inhibits collagen-induced platelet aggregation with $261.1{\mu}M$ of $IC_{50}$ and also inhibits fibrinogen binding to ${\alpha}IIb/{\beta}_3$ by a suppression of PI3K/Akt phosphorylation in a dose dependent manner. In addition, cordycepin further showed to inhibit collagen-induced p38 phosphorylation, reducing granule secretion (i.e. ATP- and serotonin-release) and thromboxane $A_2$ ($TXA_2$) production without regulating cyclooxygenase-1 (COX-1) and thromboxane A synthase (TXAS) activities, as well as phospholipase $C-{\gamma}_2$ ($PLC-{\gamma}_2$) phosphorylation. In conclusion, these results demonstrate that cordycepin-mediated antiplatelet effects were due to the inhibition of fibrinogen binding to ${\alpha}IIb/{\beta}_3$ via the suppression of PI3K/Akt phosphorylation and inhibition of granule secretion & $TXA_2$ production by suppressing p38 phosphorylation. These results strongly indicate that cordycepin might have therapeutic or preventive potential for platelet aggregation-mediated disorders, regulating the phosphoprotein, including PI3K/Akt and p38.