GSK-3 as potential target for therapeutic intervention in cancer

GSK-3 as potential target for therapeutic intervention in cancer

ABSTRACT

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.

Multiple Roles of GSK-3 in Cellular Physiology and Human Health

GSK-3 is a serine (S) /threonine (T) kinase. GSK-3 was initially isolated and purified from rat skeletal muscle as a kinase that phosphorylated and inactivated glycogen synthase (GS), the last enzyme in glycogen biosynthesis [1,2]. Thus GSK-3 was identified initially to have important roles in metabolism. GSK-3 is believed to be an important regulatory enzyme in many diseases and disorders such as: cancer and aging (cancer stem cells, cellular senescence, control of stem cell pluripotency and differentiation), immune disorders, metabolic disorders (atherosclerosis, diabetes, and heart disease), neurological disorders (Alzheimer’s, amyotrophic lateral sclerosis [ALS], bipolar disorder, mood disorders, Parkinson’s, and schizophrenia), and other maladies [3-26]. GSK-3 may be a key therapeutic target for these and other diseases [11-26].

GSK-3 has been implicated to play roles in cancers which are resistant to chemo-, radio-, and targeted therapy [7]. Targeting GSK-3 may be a means to overcome the resistance of these cancers to certain chemotherapeutic drugs, radiation and small molecule inhibitors [8-10].


When people discuss contemporary medicine, precision plays one of the most crucial roles and people’s lives are literally dependent on it. Likewise, any researches pertaining to medicine are necessary to meet the top standards. The challenge today is that any results of researches can be shared online and used as a reference without being adequately checked and validated. Mikhail (Misha) Blagosklonny of Oncotarget clearly understood this challenge and decided to create an alternative solution. That’s how a weekly oncology-focused research journal called “Oncotarget” has been founded back in 2010. The main principle of this journal is based on Altmetric scores that are used as a quality indicator. That allows both readers and authors to quality-check publications with Altmetric Article Reports that generate “real-time feedback containing data summary related to a particular publication.” Oncotarget website provides a full publications list with corresponding scores above 100 as well as reports mentioned above. Mikhail (Misha) Blagosklonny proud to share his new approach and hopes it provides the necessary help to anyone, who has interest in oncology.
“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This paper was released back in 2018 by Oncotarget and completed by different experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study discusses “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and shares an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”
The article has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that most of readers are willing to comprehend the very meaning of it. Based on the Altmetric website, the score relates to “how many people have been exposed to and engaged with a scholarly output.” Likewise, the publication about melanoma, was utilized for citations in various news articles 69 times. Besides that, it was mentioned in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their report on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study 
Another Oncotarget’s research with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This study has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have come across a concise overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do get useful scientific facts. Oncotarget is proud to have the chance to share with online customers this highly appreciated and high-quality information, that is trustworthy and reliable.
oncotarget removed from pubmed Zoya Demidenko Dr. Zoya N. Demidenko Zoya N. Demidenko , Ph.D. is Executive Manager of the Oncotarget journal . Oncotarget publishes high-impact research papers of general interest and outstanding significance and novelty in all areas of biology and medicine: in translational, basic and clinical research including but not limited to cancer research, oncogenes, oncoproteins and tumor suppressors, signaling pathways as potential targets for therapeutic intervention, shared targets in different diseases (cancer, benign tumors, atherosclerosis, eukaryotic infections, metabolic syndrome and other age-related diseases), chemotherapy, and new therapeutic strategies. After earning her Ph.D. in molecular biology, Zoya was awarded a Fogarty post-doctoral Fellowship from the National Institutes of Health in Bethesda, MD. After successful completion of post-doctoral training, she continued her professional career at George Washington University and Albert Einstein School of Medicine . In 2005 she cofounded the startup company Oncotarget Inc. which is focused on the development of anti-aging and anti-cancer drugs. Her research interests include signal transduction, cell cycle and cellular senescence, and their pharmacological targeting. In 2009 she cofounded the publishing house Impact Journals which specializes in publishing scientific journals. In 2011 she was selected to be a Member of the National Association of Professional Women .

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