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  • The diversity of biological properties and interactions

    2021-11-29

    The γ-Linolenic Acid methyl ester of biological properties and interactions of GSK-3 have been reviewed recently (, , , , ). The interactions of GSK-3 in the signaling pathways induced by nutraceuticals is covered in the review by ) in this special issue of . GSK-3 is a frequent target of many nutraceuticals such as curcumin, resveratrol and berberine. Often these nutraceuticals affect AKT activity which can inhibit GSK-3 signaling. Some of the nutraceuticals may regulate GSK-3 activity via cytokines, cytokine receptors, reactive oxygen species, microRNAs and other biochemical mechanisms. Nutraceuticals are being investigated to treat various human disorders ranging from: inflammation to cancer to diabetes, cardiovascular problems to neurodegenerative diseases. The PI3K/PTEN/Akt/mTORC1/GSK-3 pathway is important in various neurological diseases including: AD, Amyotrophic lateral sclerosis and others (, , , ; , , , , , ). Many of the target proteins of GSK-3 are associated with: immunological responses, apoptosis, EMT cancer and development. One of the key kinases which regulates GSK-3 activity is AKT. As mentioned previously AKT is serine/threonine kinase contained in the PI3K/PTEN/Akt/mTORC1/GSK-3 pathway and often involved in metabolism and cancer as well as other physiological processes (, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ). Mutations in components of this pathway (PI3K, PTEN, RAS and other upstream and downstream signaling molecules) can activate AKT which has effects on GSK-3 activity. Other biochemical mechanisms (e.g., epigenetic mechanisms) can also effect this pathway and AKT activity. Thus GSK-3 plays important roles in cancer development this is a covered extensively in this special issue of . The effects and mechanisms of GSK-3 regulation by AKT are covered by the article by ) in this special issue of . The ability of GSK-3 expression to serve as a marker and a key regulatory factor in various cancers including leukemia is covered in articles by: , ; and in this special issue in . Finally the role of GSK-3 in hepatocellular carcinoma (HCC) is covered in this special issue in in the article by ). Recently, it has been shown that the levels of GSK-3 can be a prognostic indicator in leukemia. In certain leukemias, GSK-3 has tumor-suppressor effects as it can inactivate beta-catenin, c-Myc, MCL-1 as well as other growth promoting proteins. In the review by ), the novel association between inactivation of GSK-3 and poor overall all acute myeloid leukemia (AML) patient survival is discussed. In contrast, in certain other leukemias which contain the mixed-lineage leukemia (MLL) chromosomal translocation, GSK-3 can act as a tumor promoter by inducing the phosphorylation of the cell cycle inhibitory protein p27. Thus as discussed in this review by ), GSK-3 can have both tumor promoting and tumor suppressing effects in various leukemias. Interactions between casein kinase II (CK2) and GSK-3 play important roles in leukemia and are discussed in this special issue of by ). GSK-3 and CK-2 interact to promote PTEN phosphorylation which can stimulate the activity of the PI3K/PTEN/AKT/mTORC1/GSK-3 pathway. CK-2 can also promote this pathway by transcriptional mechanisms involving the zinc-finger containing transcription factor Ikaros. Ikaros plays important roles in the hematopoietic system and is also a major tumor suppressor which is dysregulated in various leukemias. The PI3K/PTEN/AKT/mTORC1/GSK-3 pathway and certain BCL-2 family members are often dysregulated in AML. The potential for targeting of these molecules in AML is discussed in this special issue of by ). The roles of GSK-3 in HCC are controversial. The potential for targeting of these molecules in HCC is discussed in this special issue of by ). Some studies have suggested that GSK-3 can function as a tumor suppressor in HCC, while other studies indicate that inhibition of GSK-3 activity may be a therapeutic approach for HCC patients. GSK-3 activity can be influenced by many signaling pathways in HCC including, insulin-like growth factor-1, NOTCH, WNT/beta-catenin, hedgehog, transforming growth factor-beta and others.