Lithium Chloride Suppresses Colorectal Cancer Cell Survival and Proliferation through ROS/GSK-3β/NF-κB Signaling Pathway

Glycogen synthase kinase-3β(GSK-3β), a serine/threonine protein kinase, has been regarded as a potential therapeutic target for multiple human cancers. In addition, oxidative stress is closely related to all aspects of cancer. We sought to determine the biological function of lithium, one kind of GSK-3βinhibitors, in the process of reactive oxygen species (ROS) production in colorectal cancer. In this study, we analyzed the cell apoptosis and proliferation by cell viability, EdU, and flow cytometry assays through administration of LiCl. We used polymerase chain reaction and Western blotting to establish the effect of GSK-3βinhibition on the nuclear factor-κB (NF-κB) pathway. Results showed administration of LiCl increased apoptosis and the level of ROS in colorectal cancer cells. Furthermore, the underlying mechanisms could be mediated by the reduction of NF-κB expression and NF-κB-mediated transcription. Taken together, our results demonstrated that therapeutic targeting of ROS/GSK-3β/NF-κB pathways may be an effective way for colorectal cancer intervention, although further preclinical and clinical testing are desirable.

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GSK-3β in Pancreatic Cancer: Spotlight on 9-ING-41, Its Therapeutic Potential and Immune Modulatory Properties

Biology ◽

10.3390/biology10070610 ◽

2021 ◽

Vol 10 (7) ◽

pp. 610

Author(s):

Robin Park ◽

Andrew L. Coveler ◽

Ludimila Cavalcante ◽

Anwaar Saeed

Keyword(s):

Pancreatic Cancer ◽

Therapeutic Potential ◽

Glycogen Synthase ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

In Vivo Models ◽

Gsk 3Β ◽

Early Phase Clinical Trials

Glycogen synthase kinase-3 beta is a ubiquitously and constitutively expressed molecule with pleiotropic function. It acts as a protooncogene in the development of several solid tumors including pancreatic cancer through its involvement in various cellular processes including cell proliferation, survival, invasion and metastasis, as well as autophagy. Furthermore, the level of aberrant glycogen synthase kinase-3 beta expression in the nucleus is inversely correlated with tumor differentiation and survival in both in vitro and in vivo models of pancreatic cancer. Small molecule inhibitors of glycogen synthase kinase-3 beta have demonstrated therapeutic potential in pre-clinical models and are currently being evaluated in early phase clinical trials involving pancreatic cancer patients with interim results showing favorable results. Moreover, recent studies support a rationale for the combination of glycogen synthase kinase-3 beta inhibitors with chemotherapy and immunotherapy, warranting the evaluation of novel combination regimens in the future.

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Coptidis Rhizoma Extract Reverses 5-Fluorouracil Resistance in hct116 Human Colorectal Cancer Cells via Modulation of Thymidylate Synthase

Molecules ◽

10.3390/molecules26071856 ◽

2021 ◽

Vol 26 (7) ◽

pp. 1856

Author(s):

Yong-Hwi Kang ◽

Jin-Seok Lee ◽

Nam-Hun Lee ◽

Seung-Hyung Kim ◽

Chang-Seob Seo ◽

...

Keyword(s):

Colorectal Cancer ◽

Thymidylate Synthase ◽

Cell Cycle Distribution ◽

Human Colorectal Cancer ◽

Common Cancer ◽

G1 Phase Arrest ◽

Colorectal Cancer Cells ◽

Coptidis Rhizoma ◽

Underlying Mechanisms ◽

Human Colorectal Cancer Cells

Colorectal cancer (CRC) is a malignancy of the colon or rectum. It is ranked as the third most common cancer in both men and women worldwide. Early resection permitted by early detection is the best treatment, and chemotherapy is another main treatment, particularly for patients with advanced CRC. A well-known thymidylate synthase (TS) inhibitor, 5-fluorouracil (5-FU), is frequently prescribed to CRC patients; however, drug resistance is a critical limitation of its clinical application. Based on the hypothesis that Coptidis Rhizoma extract (CRE) can abolish this 5-FU resistance, we explored the efficacy and underlying mechanisms of CRE in 5-FU-resistant (HCT116/R) and parental HCT116 (HCT116/WT) cells. Compared to treatment with 5-FU alone, combination treatment with CRE and 5-FU drastically reduced the viability of HCT116/R cells. The cell cycle distribution assay showed significant induction of the G0/G1 phase arrest by co-treatment with CRE and 5-FU. In addition, the combination of CRE and 5-FU notably suppressed the activity of TS, which was overexpressed in HCT116/R cells, as compared to HCT116/WT cells. Our findings support the potential of CRE as an adjuvant agent against 5-FU-resistant colorectal cancers and indicate that the underlying mechanisms might involve inhibition of TS expression.

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PI3K/Akt/GSK-3β signal pathway is involved in P2X7 receptor-induced proliferation and EMT of colorectal cancer cells

European Journal of Pharmacology ◽

10.1016/j.ejphar.2021.174041 ◽

2021 ◽

pp. 174041

Author(s):

Wen-jun Zhang ◽

Chen Luo ◽

Chao Huang ◽

Fan-qin Pu ◽

Jin-feng Zhu ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

P2x7 Receptor ◽

Signal Pathway ◽

Colorectal Cancer Cells ◽

Gsk 3Β

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Deletion of Cardiomyocyte Glycogen Synthase Kinase-3 Beta (GSK-3β) Improves Systemic Glucose Tolerance with Maintained Heart Function in Established Obesity

Cells ◽

10.3390/cells9051120 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1120 ◽

Cited By ~ 1

Author(s):

Manisha Gupte ◽

Prachi Umbarkar ◽

Anand Prakash Singh ◽

Qinkun Zhang ◽

Sultan Tousif ◽

...

Keyword(s):

Glucose Tolerance ◽

Cardiac Function ◽

Cardiac Dysfunction ◽

Glycogen Synthase ◽

Critical Role ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Total Period ◽

Gsk 3Β

Obesity is an independent risk factor for cardiovascular diseases (CVD), including heart failure. Thus, there is an urgent need to understand the molecular mechanism of obesity-associated cardiac dysfunction. We recently reported the critical role of cardiomyocyte (CM) Glycogen Synthase Kinase-3 beta (GSK-3β) in cardiac dysfunction associated with a developing obesity model (deletion of CM-GSK-3β prior to obesity). In the present study, we investigated the role of CM-GSK-3β in a clinically more relevant model of established obesity (deletion of CM-GSK-3β after established obesity). CM-GSK-3β knockout (GSK-3βfl/flCre+/−) and controls (GSK-3βfl/flCre−/−) mice were subjected to a high-fat diet (HFD) in order to establish obesity. After 12 weeks of HFD treatment, all mice received tamoxifen injections for five consecutive days to delete GSK-3β specifically in CMs and continued on the HFD for a total period of 55 weeks. To our complete surprise, CM-GSK-3β knockout (KO) animals exhibited a globally improved glucose tolerance and maintained normal cardiac function. Mechanistically, in stark contrast to the developing obesity model, deleting CM-GSK-3β in obese animals did not adversely affect the GSK-3αS21 phosphorylation (activity) and maintained canonical β-catenin degradation pathway and cardiac function. As several GSK-3 inhibitors are in the trial to treat various chronic conditions, including metabolic diseases, these findings have important clinical implications. Specifically, our results provide critical pre-clinical data regarding the safety of GSK-3 inhibition in obese patients.

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The anti-cancer activity of an andrographolide analogue functions through a GSK-3β-independent Wnt/β-catenin signaling pathway in colorectal cancer cells

Scientific Reports ◽

10.1038/s41598-018-26278-8 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 6

Author(s):

Somrudee Reabroi ◽

Rungnapha Saeeng ◽

Nittaya Boonmuen ◽

Teerapich Kasemsuk ◽

Witchuda Saengsawang ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Anti Cancer ◽

Colorectal Cancer Cells ◽

Gsk 3Β ◽

Cancer Activity

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Glycogen Synthase Kinase 3 Phosphorylates Hypoxia-Inducible Factor 1α and Mediates Its Destabilization in a VHL-Independent Manner

Molecular and Cellular Biology ◽

10.1128/mcb.00015-07 ◽

2007 ◽

Vol 27 (9) ◽

pp. 3253-3265 ◽

Cited By ~ 134

Author(s):

Daniela Flügel ◽

Agnes Görlach ◽

Carine Michiels ◽

Thomas Kietzmann

Keyword(s):

Protein Kinase ◽

Metabolic Diseases ◽

Glycogen Synthase ◽

Protein Kinase B ◽

Hypoxia Inducible Factor ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Independent Manner ◽

Von Hippel Lindau ◽

Gsk 3Β

ABSTRACT Hypoxia-inducible transcription factor 1α (HIF-1α) is a key player in the response to hypoxia. Additionally, HIF-1α responds to growth factors and hormones which can act via protein kinase B (Akt). However, HIF-1α is not a direct substrate for this kinase. Therefore, we investigated whether the protein kinase B target glycogen synthase kinase 3 (GSK-3) may have an impact on HIF-1α. We found that the inhibition or depletion of GSK-3 induced HIF-1α whereas the overexpression of GSK-3β reduced HIF-1α. These effects were mediated via three amino acid residues in the oxygen-dependent degradation domain of HIF-1α. In addition, mutation analyses and experiments with von Hippel-Lindau (VHL)-defective cells indicated that GSK-3 mediates HIF-1α degradation in a VHL-independent manner. In line with these observations, the inhibition of the proteasome reversed the GSK-3 effects, indicating that GSK-3 may target HIF-1α to the proteasome by phosphorylation. Thus, the direct regulation of HIF-1α stability by GSK-3 may influence physiological processes or pathophysiological situations such as metabolic diseases or tumors.

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