An Inhibitor of GSK3B and HDACs Kills Pancreatic Cancer Cells and Slows Pancreatic Tumor Growth and Metastasis in Mice

Edderkaoui, Mouad; Chheda, Chintan; Soufi, Badr; Zayou, Fouzia; Hu, Robert W.; Ramanujan, V. Krishnan; Pan, Xinlei; Boros, László G.; Tajbakhsh, Jian; Madhav, Anisha; Bhowmick, Neil A.; Wang, Qiang; Lewis, Michael; Tuli, Richard; Habtezion, Aida; Murali, Ramachandran; Pandol, Stephen J.

doi:10.1053/j.gastro.2018.08.028

Cited by 65 publications

(54 citation statements)

References 55 publications

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“…These morphological changes in tumor cells induced by GSK3β inhibition coincided with the disruption of pathways that are mediated sequentially by focal adhesion kinase (FAK), guanine nucleotide exchange factors (GEFs), Rac1 and c-Jun N-terminal kinase (JNK) (reviewed in [15]). Other studies have also demonstrated the pro-invasive nature of GSK3β in colorectal, pancreatic and breast cancer cells via the modulation of cytoskeletal microstructures and cytokine-mediated extracellular matrix degradation [44,64,69]. Together, these studies provide evidence that GSK3β enhances the process of tumor invasion and probably also that of metastatic spread.…”

Section: Gsk3β and Tumor Invasionmentioning

confidence: 66%

“…To date, the tumor-promoting functions of deregulated GSK3β have been reported in 25 cancer types from various organs and tissues across the body ( Table 1 ) [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 ...…”

Section: Tumor-promoting Roles Of Gsk3β In Various Cancer Typesmentioning

confidence: 99%

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Glycogen Synthase Kinase 3β in Cancer Biology and Treatment

Domoto

Uehara

Bolidong

et al. 2020

Cells

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Glycogen synthase kinase (GSK)3β is a multifunctional serine/threonine protein kinase with more than 100 substrates and interacting molecules. GSK3β is normally active in cells and negative regulation of GSK3β activity via phosphorylation of its serine 9 residue is required for most normal cells to maintain homeostasis. Aberrant expression and activity of GSK3β contributes to the pathogenesis and progression of common recalcitrant diseases such as glucose intolerance, neurodegenerative disorders and cancer. Despite recognized roles against several proto-oncoproteins and mediators of the epithelial–mesenchymal transition, deregulated GSK3β also participates in tumor cell survival, evasion of apoptosis, proliferation and invasion, as well as sustaining cancer stemness and inducing therapy resistance. A therapeutic effect from GSK3β inhibition has been demonstrated in 25 different cancer types. Moreover, there is increasing evidence that GSK3β inhibition protects normal cells and tissues from the harmful effects associated with conventional cancer therapies. Here, we review the evidence supporting aberrant GSK3β as a hallmark property of cancer and highlight the beneficial effects of GSK3β inhibition on normal cells and tissues during cancer therapy. The biological rationale for targeting GSK3β in the treatment of cancer is also discussed at length.

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Section: Gsk3β and Tumor Invasionmentioning

confidence: 66%

Section: Tumor-promoting Roles Of Gsk3β In Various Cancer Typesmentioning

confidence: 99%

Glycogen Synthase Kinase 3β in Cancer Biology and Treatment

Domoto

Uehara

Bolidong

et al. 2020

Cells

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“…Such a relationship was also revealed in preclinical experiments on novel molecules, providing hits for further research. Metavert, an inhibitor of glycogen synthase kinase 3β and histone deacetylases, could normalize the glucose metabolism of pancreatic cancer cells and transform M2-like TAMs to the anticancer M1 phenotype in mouse models [127].…”

Section: Metabolic Crosstalk Within the Microenvironmentmentioning

confidence: 99%

Metabolism of pancreatic cancer: paving the way to better anticancer strategies

et al. 2020

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Pancreatic cancer is currently one of the most lethal diseases. In recent years, increasing evidence has shown that reprogrammed metabolism may play a critical role in the carcinogenesis, progression, treatment and prognosis of pancreatic cancer. Affected by internal or external factors, pancreatic cancer cells adopt extensively distinct metabolic processes to meet their demand for growth. Rewired glucose, amino acid and lipid metabolism and metabolic crosstalk within the tumor microenvironment contribute to unlimited pancreatic tumor progression. In addition, the metabolic reprogramming involved in pancreatic cancer resistance is also closely related to chemotherapy, radiotherapy and immunotherapy, and results in a poor prognosis. Reflective of the key role of metabolism, the number of preclinical and clinical trials about metabolism-targeted therapies for pancreatic cancer is increasing. The poor prognosis of pancreatic cancer patients might be largely improved after employing therapies that regulate metabolism. Thus, investigations of metabolism not only benefit the understanding of carcinogenesis and cancer progression but also provide new insights for treatments against pancreatic cancer.

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“…8 A recent study elucidated that glucose metabolism is involved in pancreatic tumors and that inhibition of glycogen synthase kinase 3 beta retards cancer progression in mice. 9 Alterations in metabolic protein expression and associated post-translational modification (PTM) effects may underlie the necessary adaptive changes seen in cancer cell metabolism. 10 Lysine acetylation (Kac) is an important reversible and dynamic protein PTM.…”

Section: Introductionmentioning

confidence: 99%

Insulin-like growth factor 1-induced enolase 2 deacetylation by HDAC3 promotes metastasis of pancreatic cancer

Zheng

Yang

et al. 2020

Sig Transduct Target Ther

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Enolase 2 (ENO2) is a key glycolytic enzyme in the metabolic process of glycolysis, but its potential function in pancreatic ductal adenocarcinoma (PDAC) is unclear. In this study, we observed a significant overexpression of ENO2 in PDAC tissues, and its expression was correlated with metastasis and poor prognosis in PDAC patients. K394 was identified as a major acetylation site in ENO2 that regulates its enzymatic activity, cell metabolism and PDAC progression. Knockdown of ENO2 suppressed tumor growth and liver metastasis in PDAC. Re-expression of wild-type (WT) ENO2, but not the K394 acetylation mimetic mutant, could reverse the decreased tumor malignancy. We further characterized histone deacetylase 3 (HDAC3) and P300/CBP-associated factor (PCAF) as the potential deacetylase and acetyltransferase for ENO2, respectively. HDAC3-mediated deacetylation was shown to lead to ENO2 activation and enhancement of glycolysis. Importantly, insulin-like growth factor-1 (IGF-1) was found to decrease K394 acetylation and stimulate ENO2 activity in a dose-and time-dependent manner. The PI3K/AKT/mTOR pathway facilitated the phosphorylation of HDAC3 on S424, which promoted K394 deacetylation and activation of ENO2. Linsitinib, an oral small-molecule inhibitor of IGF-1R, could inhibit IGF-1-induced ENO2 deacetylation by HDAC3 and the PI3K/AKT/mTOR pathway. Furthermore, linsitinib showed a different effect on the growth and metastasis of PDAC depending on the overexpression of WT versus K394mutant ENO2. Our results reveal a novel mechanism by which acetylation negatively regulates ENO2 activity in the metastasis of PDAC by modulating glycolysis. Blockade of IGF-1-induced ENO2 deacetylation represents a promising strategy to prevent the development of PDAC.

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An Inhibitor of GSK3B and HDACs Kills Pancreatic Cancer Cells and Slows Pancreatic Tumor Growth and Metastasis in Mice

Abstract: In studies of PDAC cells and 2 mouse models of PDAC, we found a dual inhibitor of GSK3B and HDACs (Metavert) to induce cancer cell apoptosis, reduce migration and expression of stem cell markers, and slow growth of tumors and metastases. Metavert had synergistic effects with gemcitabine.

Cited by 65 publications

References 55 publications

Glycogen Synthase Kinase 3β in Cancer Biology and Treatment

Glycogen Synthase Kinase 3β in Cancer Biology and Treatment

Metabolism of pancreatic cancer: paving the way to better anticancer strategies

Insulin-like growth factor 1-induced enolase 2 deacetylation by HDAC3 promotes metastasis of pancreatic cancer

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