The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified and studied in the regulation of glycogen synthesis. GSK-3 functions in a wide range of cellular processes. Aberrant activity of GSK-3 has been implicated in many human pathologies including: bipolar depression, Alzheimer's disease, Parkinson's disease, cancer, non-insulin-dependent diabetes mellitus (NIDDM) and others. In some cases, suppression of GSK-3 activity by phosphorylation by Akt and other kinases has been associated with cancer progression. In these cases, GSK-3 has tumor suppressor functions. In other cases, GSK-3 has been associated with tumor progression by stabilizing components of the beta-catenin complex. In these situations, GSK-3 has oncogenic properties. While many inhibitors to GSK-3 have been developed, their use remains controversial because of the ambiguous role of GSK-3 in cancer development. In this review, we will focus on the diverse roles that GSK-3 plays in various human cancers, in particular in solid tumors. Recently, GSK-3 has also been implicated in the generation of cancer stem cells in various cell types. We will also discuss how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTORC1, Ras/Raf/MEK/ERK, Wnt/beta-catenin, Hedgehog, Notch and others.

The EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance and metastasis. The expression of this pathway is frequently altered in breast cancer due to mutations at or aberrant expression of: HER2, ERalpha, BRCA1, BRCA2, EGFR1, PIK3CA, PTEN, TP53, RB as well as other oncogenes and tumor suppressor genes. In some breast cancer cases, mutations at certain components of this pathway (e.g., PIK3CA) are associated with a better prognosis than breast cancers lacking these mutations. The expression of this pathway and upstream HER2 has been associated with breast cancer initiating cells (CICs) and in some cases resistance to treatment. The anti-diabetes drug metformin can suppress the growth of breast CICs and herceptin-resistant HER2+ cells. This review will discuss the importance of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway primarily in breast cancer but will also include relevant examples from other cancer types. The targeting of this pathway will be discussed as well as clinical trials with novel small molecule inhibitors. The targeting of the hormone receptor, HER2 and EGFR1 in breast cancer will be reviewed in association with suppression of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway.

Natural products or nutraceuticals have been shown to elicit anti-aging, anti-cancer and other health-enhancing effects. A key target of the effects of natural products may be the regulation of microRNA (miR) expression which results in cell death or prevents aging, diabetes, cardiovascular and other diseases. This review will focus on a few natural products, especially on resveratrol (RES), curcumin (CUR) and berberine (BBR). RES is obtained from the skins of grapes and other fruits and berries. RES may extend human lifespan by activating the sirtuins and SIRT1 molecules. CUR is isolated from the root of turmeric (Curcuma longa). CUR is currently used in the treatment of many disorders, especially in those involving an inflammatory process. CUR and modified derivatives have been shown to have potent anti-cancer effects, especially on cancer stem cells (CSC). BBR is also isolated from various plants (e.g., Coptis chinensis) and has been used for centuries in traditional medicine to treat diseases such as adult- onset diabetes. Understanding the benefits of these and other nutraceuticals may result in approaches to improve human health.

Muscle fructose-1,6-bisphosphate aldolase (ALDOA) is among the most abundant glycolytic enzymes in all cancer cells. Here, we show that the enzyme plays a previously unknown and critical role in a cancer cell survival. Simultaneous inhibition of ALDOA activity and interaction with F-actin cytoskeleton using ALDOA slow-binding inhibitor UM0112176 leads to a rapid cofilin-dependent loss of F-actin stress fibers which is associated with elevated ROS production, inhibition of ATP synthesis, increase in calcium levels, caspase activation and arrested cellular proliferation. These effects can be reproduced by silencing of ALDOA. The mechanism of pharmacological action is, however, independent of the catalytic function of the enzyme, specific to cancer cells, and is most deleterious to cells undergoing the epithelial–mesenchymal transition, a process facilitating cancer cell invasion. Our results demonstrate that the overabundance of ALDOA in cancer cells is associated with its moonlighting rather than catalytic functions. This may have significant implications for development of novel broad-based anti-cancer therapies.

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Edited by Judit OvádiKeywords: FBPase Mitochondria GSK3 Calcium Cardiomyocyte Hypertrophy a b s t r a c t A growing body of research suggests that fructose 1,6-bisphosphatase (FBPase) might be involved in regulation of cell mortality/survival. However, the precise role of FBPase in the process remains unknown. Here, we show for the first time that in HL-1 cardiomyocytes, inhibition of glycogen synthase kinase-3 results in translocation of FBPase to mitochondria. In vitro experiments demonstrate that FBPase reduces the rate of calcium-induced mitochondrial swelling, affects ATP synthesis and interacts with mitochondrial proteins involved in regulation of volume and energy homeostasis. We suggest that FBPase might be engaged in a regulation of cell survival by influencing mitochondrial function. Structured summary of protein interactions:FBPase physically interacts with VDAC2, Vdac3, ATP synthase subunit beta, Slc25a5, ATP synthase subunit alpha, Histone cluster 1, H1d, Histone H2A, Histone H4 and Histone H3 by affinity chromatography technology (View interaction) FBPase physically interacts with ATP synthase subunit b, ATP synthase subunit a, ADP/ATP translocase 1, ADP/ATP translocase 2 and VDAC2 by cross-linking study (View interaction)

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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...