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DESC1, a novel tumor suppressor, sensitizes cells to apoptosis by downregulating the EGFR/AKT pathway in esophageal squamous cell carcinoma.

Esophageal cancer is ranked as the eighth most common cancer and the sixth leading cause of cancer deaths worldwide. To identify candidate tumor suppressor genes related to esophageal squamous cell carcinoma (ESCC) development, a cDNA microarray analysis was performed using paired tumor and nontumor tissue samples from ESCC patients. Differentially expressed in squamous cell carcinoma 1 (DESC1), which belongs to the Type II transmembrane serine protease family, was frequently downregulated in ESCC. This study aims to elucidate the molecular mechanism for the tumor suppressive function of DESC1 in ESCC. We show that DESC1 reduced cell viability and sensitized cells to apoptosis, when cells were under apoptotic stimuli. The proapoptotic effect of DESC1 was mediated through downregulating AKT1 activation and the restoration of AKT activation by the introduction of the constitutively active AKT, myr-AKT, abolished the apoptosis-sensitizing effect of DESC1. DESC1 also reduced EGFR protein level, which was abrogated when the proteolytic function of DESC1 was lost, suggesting that DESC1 cleaved EGFR and downregulated the EGFR/AKT pathway to favor apoptosis. The transmembrane localization and the structural domains provide an opportunity for DESC1 to interact with the extracellular environment. The importance of such interaction was highlighted by the finding that DESC1 reduced cell colony formation ability in three-dimensional culture. In line with this, DESC1 reduced tumor growth kinetics in the in vivo orthotopic tumorigenesis assay. Taken together, our novel findings suggest how DESC1 may suppress ESCC development by sensitizing cells to apoptosis under an apoptotic stimulus through downregulating the EGFR/AKT signaling pathway.

1018 related Products with: DESC1, a novel tumor suppressor, sensitizes cells to apoptosis by downregulating the EGFR/AKT pathway in esophageal squamous cell carcinoma.

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Prediabetes linked to excess glucagon in transgenic mice with pancreatic active AKT1.

Protein kinase B/AKT has three isoforms (AKT1-3) and is renowned for its central role in the regulation of cell growth and proliferation, due to its constitutive activation in various cancers. AKT2, which is highly expressed in insulin-responsive tissues, has been identified as a primary regulator of glucose metabolism as Akt2 knockout mice (Akt2(-/-)) are glucose-intolerant and insulin-resistant. However, the role of AKT1 in glucose metabolism is not as clearly defined. We previously showed that mice with myristoylated Akt1 (AKT1(Myr)) expressed through a bicistronic Pdx1-TetA and TetO-MyrAkt1 system were susceptible to islet cell carcinomas, and in this study we characterized an early onset, prediabetic phenotype. Beginning at weaning (3 weeks of age), the glucose-intolerant AKT1(Myr) mice exhibited non-fasted hyperglycemia, which progressed to fasted hyperglycemia by 5 months of age. The glucose intolerance was attributed to a fasted hyperglucagonemia, and hepatic insulin resistance detectable by reduced phosphorylation of the insulin receptor following insulin injection into the inferior vena cava. In contrast, treatment with doxycycline diet to turn off the transgene caused attenuation of the non-fasted and fasted hyperglycemia, thus affirming AKT1 hyperactivation as the trigger. Collectively, this model highlights a novel glucagon-mediated mechanism by which AKT1 hyperactivation affects glucose homeostasis and provides an avenue to better delineate the molecular mechanisms responsible for diabetes mellitus and the potential association with pancreatic cancer.

2362 related Products with: Prediabetes linked to excess glucagon in transgenic mice with pancreatic active AKT1.

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Constitutively active Akt1 cooperates with KRas(G12D) to accelerate in vivo pancreatic tumor onset and progression.

Pancreatic adenocarcinoma is a deadly disease characterized by metastatic progression and resistance to conventional therapeutics. Mutation of KRAS is the most frequent early event in pancreatic tumor progression. AKT isoforms are frequently activated in pancreatic cancer, and reports have implicated hyperactivation of AKT1, as well as AKT2, in pancreatic tumor formation. The objective here is to delineate the role of AKT in facilitating in vivo pancreatic tumor progression in the context of KRAS mutation and predisposition to pancreatic cancer.

1191 related Products with: Constitutively active Akt1 cooperates with KRas(G12D) to accelerate in vivo pancreatic tumor onset and progression.

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SKP2 cooperates with N-Ras or AKT to induce liver tumor development in mice.

Mounting evidence indicates that S-Phase Kinase-Associated Protein 2 (SKP2) is overexpressed in human hepatocellular carcinoma (HCC). However, the role of SKP2 in hepatocarcinogenesis remains poorly delineated. To elucidate the function(s) of SKP2 in HCC, we stably overexpressed the SKP2 gene in the mouse liver, either alone or in combination with activated forms of N-Ras (N-RasV12), AKT1 (myr-AKT1), or β-catenin (ΔN90-β-catenin) protooncogenes, via hydrodynamic gene delivery. We found that forced overexpression of SKP2, N-RasV12 or ΔN90-β-catenin alone as well as co-expression of SKP2 and ΔN90-β-catenin did not induce liver tumor development. Overexpression of myr-AKT1 alone led to liver tumor development after long latency. In contrast, co-expression of SKP2 with N-RasV12 or myr-AKT1 resulted in early development of multiple hepatocellular tumors in all SKP2/N-RasV12 and SKP2/myr-AKT1 mice. At the molecular level, preneoplastic and neoplastic liver lesions from SKP2/N-RasV12 and SKP2/myr-AKT1 mice exhibited a strong induction of AKT/mTOR and Ras/MAPK pathways. Noticeably, the tumor suppressor proteins whose levels have been shown to be downregulated by SKP2-dependent degradation in various tumor types, including p27, p57, Dusp1, and Rassf1A were not decreased in liver lesions from SKP2/N-RasV12 and SKP2/myr-AKT1 mice. In human HCC specimens, nuclear translocation of SKP2 was associated with activation of the AKT/mTOR and Ras/MAPK pathways, but not with β-catenin mutation or activation. Altogether, the present data indicate that SKP2 cooperates with N-Ras and AKT proto-oncogenes to promote hepatocarcinogenesis in vivo.

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Activation of Akt1 accelerates carcinogen-induced tumorigenesis in mammary gland of virgin and post-lactating transgenic mice.

Data from in vivo and in vitro studies suggest that activation of Akt regulates cell survival signaling and plays a key role in tumorigenesis. Hence, transgenic mice were created to explore the oncogenic role of Akt1 in the development of mammary tumors.

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Aspp2 negatively regulates body growth but not developmental timing by modulating IRS signaling in zebrafish embryos.

The growth and developmental rate of developing embryos and fetus are tightly controlled and coordinated to maintain proper body shape and size. The insulin receptor substrate (IRS) proteins, key intracellular transducers of insulin and insulin-like growth factor signaling, play essential roles in the regulation of growth and development. A short isoform of apoptosis-stimulating protein of p53 2 (ASPP2) was recently identified as a binding partner of IRS-1 and IRS-2 in mammalian cells in vitro. However, it is unclear whether ASPP2 plays any role in vertebrate embryonic growth and development. Here, we show that zebrafish Aspp2a and Aspp2b negatively regulate embryonic growth without affecting developmental rate. Human ASPP2 had similar effects on body growth in zebrafish embryos. Aspp2a and 2b inhibit Akt signaling. This inhibition was reversed by coinjection of myr-Akt1, a constitutively active form of Akt1. Zebrafish Aspp2a and Aspp2b physically bound with Irs-1, and the growth inhibitory effects of ASPP2/Aspp2 depend on the presence of their ankyrin repeats and SH3 domains. These findings uncover a novel role of Aspp2 in regulating vertebrate embryonic growth.

2043 related Products with: Aspp2 negatively regulates body growth but not developmental timing by modulating IRS signaling in zebrafish embryos.

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Inhibition of the PI3K/Akt/GSK3 pathway downstream of BCR/ABL, Jak2-V617F, or FLT3-ITD downregulates DNA damage-induced Chk1 activation as well as G2/M arrest and prominently enhances induction of apoptosis.

Constitutively-activated tyrosine kinase mutants, such as BCR/ABL, FLT3-ITD, and Jak2-V617F, play important roles in pathogenesis of hematopoietic malignancies and in acquisition of therapy resistance. We previously found that hematopoietic cytokines enhance activation of the checkpoint kinase Chk1 in DNA-damaged hematopoietic cells by inactivating GSK3 through the PI3K/Akt signaling pathway to inhibit apoptosis. Here we examine the possibility that the kinase mutants may also protect DNA-damaged cells by enhancing Chk1 activation. In cells expressing BCR/ABL, FLT3-ITD, or Jak2-V617F, etoposide induced a sustained activation of Chk1, thus leading to the G2/M arrest of cells. Inhibition of these kinases by their inhibitors, imatinib, sorafenib, or JakI-1, significantly abbreviated Chk1 activation, and drastically enhanced apoptosis induced by etoposide. The PI3K inhibitor GD-0941 or the Akt inhibitor MK-2206 showed similar effects with imatinib on etoposide-treated BCR/ABL-expressing cells, including those expressing the imatinib-resistant T315I mutant, while expression of the constitutively activated Akt1-myr mutant conferred resistance to the combined treatment of etoposide and imatinib. GSK3 inhibitors, including LiCl and SB216763, restored the sustained Chk1 activation and mitigated apoptosis in cells treated with etoposide and the inhibitors for aberrant kinases, PI3K, or Akt. These observations raise a possilibity that the aberrant kinases BCR/ABL, FLT3-ITD, and Jak2-V617F may prevent apoptosis induced by DNA-damaging chemotherapeutics, at least partly through enhancement of the Chk1-mediated G2/M checkpoint activation, by inactivating GSK3 through the PI3K/Akt signaling pathway. These results shed light on the molecular mechanisms for chemoresistance of hematological malignancies and provide a rationale for the combined treatment with chemotherapy and the tyrosine kinase or PI3K/Akt pathway inhibitors against these diseases.

2915 related Products with: Inhibition of the PI3K/Akt/GSK3 pathway downstream of BCR/ABL, Jak2-V617F, or FLT3-ITD downregulates DNA damage-induced Chk1 activation as well as G2/M arrest and prominently enhances induction of apoptosis.

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Brassinin induces apoptosis in PC-3 human prostate cancer cells through the suppression of PI3K/Akt/mTOR/S6K1 signaling cascades.

The oncogenic PI3K/Akt/mammalian target of rapamycin (mTOR) signaling axis and its downstream effector, the ribosomal protein S6 kinase 1 (S6K1) play a key role in mediating cell survival in various tumor cells. Here, we investigated the effects of brassinin (BSN), a phytoalexin first identified as a constituent of cabbage, on the PI3K/Akt/mTOR/S6K1 activation, cellular proliferation, and apoptosis in PC-3 human prostate cancer. BSN exerted a significant dose-dependent cytotoxicity and reduced constitutive phosphorylation of Akt against androgen-independent PC-3 cells as compared to androgen-dependent LNCaP cells. Moreover, knockdown of androgen receptor (AR) by small interfering RNA enhanced the potential effect of BSN on induction of apoptosis in LNCaP cells. BSN clearly suppressed the constitutive activation of PI3K/Akt/mTOR/S6K1 signaling cascade, which correlated with the induction of apoptosis as characterized by accumulation of cells in subG1 phase, positive Annexin V binding, TUNEL staining, loss of mitochondrial membrane potential, down-regulation of antiapoptotic and proliferative proteins, activation of caspase-3, and cleavage of PARP. Additionally, BSN could block broad-spectrum inhibition of PI3K/Akt/mTOR/S6K1 axes, and aberrant Akt activation by pcDNA3-myr-HA-Akt1 plasmid could not prevent the observed suppressive effect of BSN on constitutive mTOR activation. Finally, overexpression of Bcl-2 also attenuated BSN-mediated apoptosis in PC-3 cells. Taken together, our findings suggest that BSN can interfere with multiple signaling cascades involved in tumorigenesis and might be provided as a potential therapeutic candidate for both the prevention and treatment of prostate cancer.

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Magnetic force-based cell patterning for evaluation of the effect of stromal fibroblasts on invasive capacity in 3D cultures.

Biomimetic cell culture systems that recreate tumor microenvironments are necessary in understanding the progression of cancer cells in cell-to-cell interaction and in cell-to-extracellular matrix interaction. We have developed a three-dimensional spheroid array embedded in collagen for evaluation of the effect of stromal fibroblasts associated with cancer cells. When the breast epithelial cancer cell model MCF10A/myr-Akt1 was magnetically labeled and aligned in the array by an external magnetic force using a pin-holder device and a magnet, a stellate configuration was observed. Changes in MCF10A/myr-Akt1 cell behavior were only slight when normal human dermal fibroblasts (NHDF) cells coexisted in collagen (indirect-interaction array). In contrast, when NHDF were magnetically labeled and patterned together with MCF10A/myr-Akt1 (direct-interaction array), spreading and progression were observed along with NHDF. Cell image analysis indicated that the length and area were statistically significantly increased in the direct-interaction array compared to the MCF10A/myr-Akt1 alone or to the indirect-interaction array. A cell susceptibility assay was undertaken with breast cancer MDA-MB-231 associated with NHDF in the indirect-interaction array. Interestingly, although distinct suppression of cell movement and proliferation was observed with 100 μM of collagenase inhibitor, formation of invadepodia significantly increased with coexistent NHDF. Since cancer progression is influenced by its microenvironment, this magnetic cell-patterning method which clarifies direct and indirect effects of stromal cells on invasion and proliferation, is well suited for evaluation and design of more efficient approaches in cancer prevention and treatment.

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Survival and death signals can predict tumor response to therapy after oncogene inactivation.

Cancers can exhibit marked tumor regression after oncogene inhibition through a phenomenon called "oncogene addiction." The ability to predict when a tumor will exhibit oncogene addiction would be useful in the development of targeted therapeutics. Oncogene addiction is likely the consequence of many cellular programs. However, we reasoned that many of these inputs may converge on aggregate survival and death signals. To test this, we examined conditional transgenic models of K-ras(G12D)--or MYC-induced lung tumors and lymphoma combined with quantitative imaging and an in situ analysis of biomarkers of proliferation and apoptotic signaling. We then used computational modeling based on ordinary differential equations (ODEs) to show that oncogene addiction could be modeled as differential changes in survival and death intracellular signals. Our mathematical model could be generalized to different imaging methods (computed tomography and bioluminescence imaging), different oncogenes (K-ras(G12D) and MYC), and several tumor types (lung and lymphoma). Our ODE model could predict the differential dynamics of several putative prosurvival and prodeath signaling factors [phosphorylated extracellular signal-regulated kinase 1 and 2, Akt1, Stat3/5 (signal transducer and activator of transcription 3/5), and p38] that contribute to the aggregate survival and death signals after oncogene inactivation. Furthermore, we could predict the influence of specific genetic lesions (p53⁻/⁻, Stat3-d358L, and myr-Akt1) on tumor regression after oncogene inactivation. Then, using machine learning based on support vector machine, we applied quantitative imaging methods to human patients to predict both their EGFR genotype and their progression-free survival after treatment with the targeted therapeutic erlotinib. Hence, the consequences of oncogene inactivation can be accurately modeled on the basis of a relatively small number of parameters that may predict when targeted therapeutics will elicit oncogene addiction after oncogene inactivation and hence tumor regression.

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