Glycogen synthase kinases: Moonlighting proteins with theranostic potential in cancer

Nagini, Siddavaram; Sophia, Josephraj; Mishra, Rajakishore

doi:10.1016/j.semcancer.2017.12.010

Cited by 95 publications

(89 citation statements)

References 116 publications

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“…Strict insulin inhibition can result in two principle effects, both of which have the potential to induce cancer cell programmed cell death and to reduce proliferation of cancer cells. First, reduced blood insulin concentrations at the cancer cell membrane results in less binding to the insulin receptor with resulting downstream inhibition of the PI3K-Akt-mTOR (PAM) signaling cascade [22], as well as the RAS-RAF-MEK-ERK pathway [23]. We therefore propose that reduced insulin concentration due to a ketogenic diet provides the potential to enhance programmed cell death by inhibiting the PAM cascade, and to reduce proliferation via both pathways [24] [25].…”

Section: Discussionmentioning

confidence: 99%

The Effect of a Ketogenic Diet and Synergy with Rapamycin in a Mouse Model of Breast Cancer

Zou

Fineberg

Pearlman

et al. 2020

Preprint

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14 Background: The effects of diet in cancer, in general, and breast cancer in particular, 15 are not well understood. Insulin inhibition in ketogenic, high fat diets, modulate 16 downstream signaling molecules and are postulated to have therapeutic benefits.17 Obesity and diabetes have been associated with higher incidence of breast cancer.18 Addition of anti-cancer drugs together with diet is also not well studied.19 Methods: Two diets, one ketogenic, the other standard mouse chow, were tested in a 20 spontaneous breast cancer model in mice. The diets were implemented either with or 21 without added rapamycin, an mTOR inhibitor and potential anti-cancer drug.22 Results: Blood glucose and insulin concentrations in mice ingesting the ketogenic diet 23 (KD) were significantly lower, whereas beta hydroxybutyrate (BHB) levels were 24 significantly higher, respectively, than in mice on the standard diet (SD). Growth of 25 primary breast tumors and lung metastases were inhibited, and lifespans were longer in 26 the KD mice compared to mice on the SD (p<0.005). Rapamycin improved survival in 27 both mouse diet groups, but when combined with the KD was more effective than when 28 combined with the SD.29 Conclusions: The study provides proof of principle that a ketogenic diet a) results in 30 serum insulin reduction and ketosis in a spontaneous breast cancer mouse model; b) 31 can serve as a therapeutic anti-cancer agent; and c) can enhance the effects of 32 rapamycin, an anti-cancer drug, permitting dose reduction for comparable effect.33 Further, the ketogenic diet in this model produces superior cancer control than standard 34 mouse chow whether with or without added rapamycin. 36 Introduction 37Insulin inhibition by a ketogenic diet has been shown to slow cancer growth and 38 prolong survival in animal models and has shown safety and feasibility in small pilot 39 studies in humans [1], [2] [3] [4] . We previously demonstrated in a pilot study of ten 40 people with diverse, metastatic PET positive cancers that higher levels of ketosis 41 correlated with stability vs. disease progression [5]. The full potential of ketosis in 42 cancer therapy, however, may reside in its potential to synergize with anti-cancer drugs 43 and other modalities of treatment. Increased overall efficacy may permit lower drug 44 doses, thereby reducing their toxicities and side effects. Accordingly, it may be possible 45 that the overall improvement in therapy will result in extended survival with a better 46 quality of life. 47 An understanding of ketogenic diets (KD) in cancer is limited at this point but it 48 seems unlikely that KDs by themselves can control all the features of the oncogenic 49 state. There is much interest, therefore, in the possibility of synergy with other drugs or 50 other therapies. Hsieh, et al., for example, demonstrated that a squamous cell 51 carcinoma that over expressed GLUT1 receptors showed attenuated growth when 52 animals were on a KD [6]. There was, however, little regression of tumors. The addition 53 of th...

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Section: Discussionmentioning

confidence: 99%

The Effect of a Ketogenic Diet and Synergy with Rapamycin in a Mouse Model of Breast Cancer

Zou

Fineberg

Pearlman

et al. 2020

Preprint

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“…Moreover, GSK3β renders cancer cells insensitive to chemotherapeutics and ionizing radiation . Our observations and other studies establish GSK3β as a common and attractive therapeutic target for a broad spectrum of chronic diseases including cancer . A therapeutic effect from GSK3β inhibition has been shown not only in epithelial but also in hematopoietic, neuronal and musculoskeletal malignancies, including rhabdomyosarcoma and osteosarcoma .…”

Section: Introductionmentioning

confidence: 99%

Glycogen synthase kinase 3β as a potential therapeutic target in synovial sarcoma and fibrosarcoma

et al. 2019

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derived growth factor; pGSK3β S9 , GSK3β phosphorylated in S9 residue; pGSK3β Y216 , GSK3β phosphorylated in Y216 residue; RTK(s), receptor-type tyrosine kinase(s) AbstractSoft tissue sarcomas (STSs) are a rare cancer type. Almost half are unresponsive to multi-pronged treatment and might therefore benefit from biologically targeted therapy. An emerging target is glycogen synthase kinase (GSK)3β, which is implicated in various diseases including cancer. Here, we investigated the expression, activity and putative pathological role of GSK3β in synovial sarcoma and fibrosarcoma, comprising the majority of STS that are encountered in orthopedics. Expression of the active form of GSK3β (tyrosine 216-phosphorylated) was higher in synovial sarcoma (SYO-1, HS-SY-II, SW982) and in fibrosarcoma (HT1080) tumor cell lines than in untransformed fibroblast (NHDF) cells that are assumed to be the normal mesenchymal counterpart cells. Inhibition of GSK3β activity by pharmacological agents (AR-A014418, SB-216763) or of its expression by RNA interference suppressed the proliferation of sarcoma cells and their invasion of collagen gel, as well as inducing their apoptosis.These effects were associated with G0/G1-phase cell cycle arrest and decreased expression of cyclin D1, cyclin-dependent kinase (CDK)4 and matrix metalloproteinase 2. Intraperitoneal injection of the GSK3β inhibitors attenuated the growth of SYO-1 and HT1080 xenografts in athymic mice without obvious detrimental effects. It also mitigated cell proliferation and induced apoptosis in the tumors of mice. This study indicates that increased activity of GSK3β in synovial sarcoma and fibrosarcoma sustains tumor proliferation and invasion through the cyclin D1/CDK4-mediated pathway and enhanced extracellular matrix degradation. Our results provide a biological basis for GSK3β as a new and promising therapeutic target for these STS types. K E Y W O R D Scell cycle, glycogen synthase kinase 3β, invasion, migration, soft tissue sarcoma

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“…The activity of GSK3β affects energy metabolism, cell survival, proliferation, apoptosis, membrane polarity, internalization of the synaptic receptors, neuroplasticity, neurotransmission, amyloid processing, and many other processes [13].Extracellular factors, such as insulin or insulin-like growth factor 1 (IGF-1), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and transforming growth factor 1β (TGF-1β), acting via the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, inhibit GSK3β by phosphorylation of Ser9 of the kinase [14][15][16]. The same effect is mediated by mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway activity upon EGF, fibroblast growth factor (FGF), PDGF, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) stimulation, and as a result of cytokine action via p38 MAPK [17][18][19]. Inactivation of GSK3β may also be an effect of protein kinase A (PKA) activity (stimulated by.…”

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GSK3β: A Master Player in Depressive Disorder Pathogenesis and Treatment Responsiveness

Duda

Hajka

Wójcicka

et al. 2020

Cells

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Glycogen synthase kinase 3β (GSK3β), originally described as a negative regulator of glycogen synthesis, is a molecular hub linking numerous signaling pathways in a cell. Specific GSK3β inhibitors have anti-depressant effects and reduce depressive-like behavior in animal models of depression. Therefore, GSK3β is suggested to be engaged in the pathogenesis of major depressive disorder, and to be a target and/or modifier of anti-depressants' action. In this review, we discuss abnormalities in the activity of GSK3β and its upstream regulators in different brain regions during depressive episodes. Additionally, putative role(s) of GSK3β in the pathogenesis of depression and the influence of anti-depressants on GSK3β activity are discussed.Cells 2020, 9, 727 2 of 26 any of the groups listed above. Additionally, electroconvulsive therapy, conducted for the first time in 1938, is still widely used in the treatment of MDD, especially in its drug-refractory form [5].Although the monoaminergic hypothesis has led to the invention of many successful therapeutic strategies based on the elevation of levels of NA and 5-HT in the synaptic cleft, it does not explain the anti-depressant effect of lithium and the rapid action of ketamine in the treatment of mood disorders [6]. Therefore, factors other than neurotransmission must be taken into consideration in the context of the MDD pathogenesis. One of them is glycogen synthase kinase 3β (GSK3β) signaling. Glycogen Synthase Kinase 3βGSK3 was isolated in 1980, from rabbit skeletal muscle, and described as a highly specific serine/threonine kinase for glycogen synthase [7]. There are two isozymes of GSK3, α and β, and both are expressed at similar levels in the mouse brain [8]. In the human brain, the β isozyme predominates [9]. Therefore, GSK3β is expected to be crucial for the human central nervous system functioning. The activity of GSK3β is regulated positively and negatively by phosphorylation on Tyr216 and Ser9, respectively [10,11]. Whereas phosphorylation of the residue Tyr216 occurs during the GSK3β translation process and results in a synthesis of the fully activated kinase, Ser9 phosphorylation seems to be the main regulatory modification during the enzyme lifespan [12]. Ser9-phosphorylated GSK3β remains inhibited, and dephosphorylation of the residue results in the disinhibition (activation) of the kinase.GSK3β is part of numerous cellular signaling pathways, and its activity can be regulated, directly or indirectly, by several kinases, phosphatases, and proteases. The wide spectrum of GSK3β substrates, including transcription factors, glycolytic enzymes, pro-and anti-apoptotic factors, mitochondrial channels, membrane receptors, and cytoskeleton-associated proteins, makes GSK3β a central point of the cell homeostasis maintenance [13]. The activity of GSK3β affects energy metabolism, cell survival, proliferation, apoptosis, membrane polarity, internalization of the synaptic receptors, neuroplasticity, neurotransmission, amyloid processing, and many other processes [13].Ex...

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Glycogen synthase kinases: Moonlighting proteins with theranostic potential in cancer

Cited by 95 publications

References 116 publications

The Effect of a Ketogenic Diet and Synergy with Rapamycin in a Mouse Model of Breast Cancer

The Effect of a Ketogenic Diet and Synergy with Rapamycin in a Mouse Model of Breast Cancer

Glycogen synthase kinase 3β as a potential therapeutic target in synovial sarcoma and fibrosarcoma

GSK3β: A Master Player in Depressive Disorder Pathogenesis and Treatment Responsiveness

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