Crosstalk between Raf/MEK/ERK and PI3K/AKT in Suppression of Bax Conformational Change by Grp75 under Glucose Deprivation Conditions

Yang, Ling; Guo, Weiwei; Zhang, Qunling; Li, Hongyan; Liu, Xiaoyu; Yang, Yunlong; Zuo, Jiane; Liu, Wen

doi:10.1016/j.jmb.2011.09.009

Cited by 56 publications

(42 citation statements)

References 32 publications

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“…Although primary breast cancer is often treated with surgery and radiation, it is the later stage when cells escape treatment due to chemoresistance and metastasis to the brain, bones, liver, and lungs. Mortalin was shown to activate telomerase, hnRNP-K, E2F1A, and PI3K/AKT proteins (23,37,38). In agreement with these known functions of mortalin, it has been detected as an upregulated protein in a variety of human tumors.…”

Section: Discussionmentioning

confidence: 66%

“…Overexpression of miR19a was also shown to activate PI3K/AKT signaling, and induced EMT in gastric cancers (43). Overexpression of mortalin was earlier shown to inactivate p53, activate telomerase, and antiapoptotic signaling through Raf/MEK/ERK pathway and inhibition of conformational change of Bax (17,18,38), and to mediate erythropoietin-induced growth of erythroid progenitor cells ( Fig. 7D; ref.…”

Section: Discussionmentioning

confidence: 79%

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Stress Chaperone Mortalin Contributes to Epithelial-to-Mesenchymal Transition and Cancer Metastasis

Kaul

Ryu

et al. 2016

Cancer Research

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Mortalin/mthsp70 (HSPA9) is a stress chaperone enriched in many cancers that has been implicated in carcinogenesis by promoting cell proliferation and survival. In this study, we examined the clinical relevance of mortalin upregulation in carcinogenesis. Consistent with high mortalin expression in various human tumors and cell lines, we found that mortalin overexpression increased the migration and invasiveness of breast cancer cells. Expression analyses revealed that proteins involved in focal adhesion, PI3K-Akt, and JAK-STAT signaling, all known to play key roles in cell migration and epithelial-tomesenchymal transition (EMT), were upregulated in mortalinexpressing cancer cells. We further determined that expression levels of the mesenchymal markers vimentin (VIM), fibronectin (FN1), b-catenin (CTNNB1), CK14 (KRT14), and hnRNP-K were also increased upon mortalin overexpression, whereas the epithelial markers E-cadherin (CDH1), CK8 (KRT8), and CK18 (KRT18) were downregulated. Furthermore, shRNAmediated and pharmacologic inhibition of mortalin suppressed the migration and invasive capacity of cancer cells and was associated with a diminished EMT gene signature. Taken together, these findings support a role for mortalin in the induction of EMT, prompting further investigation of its therapeutic value in metastatic disease models. Cancer Res; 76(9);

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 79%

Stress Chaperone Mortalin Contributes to Epithelial-to-Mesenchymal Transition and Cancer Metastasis

Kaul

Ryu

et al. 2016

Cancer Research

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“…Pharmacologic inhibition of MEK following selumetinib treatment not only inhibited the activation of ERK, but also enhanced AKT activation. The MEK/ERK and PI3K/Akt signaling pathways interact with each other (36,37). Differentiated myofibers were simultaneously regulated in response to the same stimulant, but exerted opposing effects (33).…”

Section: Discussionmentioning

confidence: 99%

Selumetinib Attenuates Skeletal Muscle Wasting in Murine Cachexia Model through ERK Inhibition and AKT Activation

Yang

Huo

Han

et al. 2017

Molecular Cancer Therapeutics

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Cancer cachexia is a multifactorial syndrome affecting the skeletal muscle. Previous clinical trials showed that treatment with MEK inhibitor selumetinib resulted in skeletal muscle anabolism. However, it is conflicting that MAPK/ERK pathway controls the mass of the skeletal muscle. The current study investigated the therapeutic effect and mechanisms of selumetinib in amelioration of cancer cachexia. The classical cancer cachexia model was established via transplantation of CT26 colon adenocarcinoma cells into BALB/c mice. The effect of selumetinib on body weight, tumor growth, skeletal muscle, food intake, serum proinflammatory cytokines, E3 ligases, and MEK/ERK-related pathways was analyzed. Two independent experiments showed that 30 mg/kg/d selumetinib prevented the loss of body weight in murine cachexia mice. Muscle wasting was attenuated and the expression of E3 ligases, MuRF1 and Fbx32, was inhibited following selumetinib treatment of the gastrocnemius muscle. Furthermore, selumetinib efficiently reduced tumor burden without influencing the cancer cell proliferation, cumulative food intake, and serum cytokines. These results indicated that the role of selumetinib in attenuating muscle wasting was independent of cancer burden. Detailed analysis of the mechanism revealed AKT and mTOR were activated, while ERK, FoxO3a, and GSK3b were inhibited in the selumetinib -treated cachexia group. These indicated that selumetinib effectively prevented skeletal muscle wasting in cancer cachexia model through ERK inhibition and AKT activation in gastrocnemius muscle via cross-inhibition. The study not only elucidated the mechanism of MEK/ERK inhibition in skeletal muscle anabolism, but also validated selumetinib therapy as an effective intervention against cancer cachexia.

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“…Consistently, our results showed that both p-Akt and p-ERK expression were up-regulated by FAM3A overexpression, suggesting the possible involvement of these cascades in FAM3A induced protection. Akt has been known as an endogenous protective factor against cell death in many kinds of insults, and it can inhibit apoptosis in many ways, both upstream and downstream of mitochondrial perturbation [26]. In contrast, the role of ERK in cell death was disputable.…”

Section: Discussionmentioning

confidence: 99%

FAM3A Protects HT22 Cells Against Hydrogen Peroxide-Induced Oxidative Stress Through Activation of PI3K/Akt but not MEK/ERK Pathway

Song¹,

Gou²,

Zhang³

2015

Cell Physiol Biochem

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Background/Aims: Oxidative stress-induced cell damage is involved in many neurological diseases. FAM3A is the first member of family with sequence similarity 3 (FAM3) gene family and its biological function remains largely unknown. Methods: This study aimed to determine its role in hydrogen peroxide (H₂O₂) induced injury in neuronal HT22 cells. The protective effects were measured by cell viability, lactate dehydrogenase (LDH) release and apoptosis, and oxidative stress was assayed by reactive oxygen species (ROS) generation, ATP synthesis and lipid peroxidation. By using selective inhibitors, the involvement of PI3K/Akt and MEK/ERK pathways were also investigated. Results: The results of fluorescence staining revealed that H₂O₂ significantly decreased the expression of FAM3A protein, which was shown to be subcellularly located in mitochondria. Up-regulation of FAM3A by lentivirus transfection markedly increased cell viability and decreased LDH release after H₂O₂ treatment. The anti-apoptotic activity of FAM3A was demonstrated by the reduced mitochondrial cytochrome c release, decreased activation of caspase-3 and the results of flow cytometry. Overexpression of FAM3A attenuated intracellular ROS generation and loss of ATP production induced by H₂O₂, and subsequently inhibited lipid peroxidation. In addition, overexpression of FAM3A significantly increased the activation of Akt and ERK in H₂O₂ injured HT22 cells. By using Akt and ERK specific inhibitors, we found that inhibition of PI3K/Akt, but not MEK/ERK pathway, partially prevented FAM3A-induced protection against H₂O₂. Conclusion: These results suggest that FAM3A has protective effects against H₂O₂-induced oxidative stress by reducing ROS accumulation and apoptosis, and these protective effects are dependent on the activation of PI3K/Akt pathway.

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Crosstalk between Raf/MEK/ERK and PI3K/AKT in Suppression of Bax Conformational Change by Grp75 under Glucose Deprivation Conditions

Cited by 56 publications

References 32 publications

Stress Chaperone Mortalin Contributes to Epithelial-to-Mesenchymal Transition and Cancer Metastasis

Stress Chaperone Mortalin Contributes to Epithelial-to-Mesenchymal Transition and Cancer Metastasis

Selumetinib Attenuates Skeletal Muscle Wasting in Murine Cachexia Model through ERK Inhibition and AKT Activation

FAM3A Protects HT22 Cells Against Hydrogen Peroxide-Induced Oxidative Stress Through Activation of PI3K/Akt but not MEK/ERK Pathway

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