Glycogen synthase kinase-3β: a novel therapeutic target for pancreatic cancer

Ding, Li; Billadeau, Daniel D.

doi:10.1080/14728222.2020.1743681

Cited by 28 publications

(29 citation statements)

References 93 publications

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“…In the present study, the effect of extracellular IL-33 at a high concentration (20 ng/ml) from either cancer cells or CAFs released into the tumor microenvironment of CCA inhibited cancer cell migration. This is supported by the previous finding that IL-33 ligating to its receptor could inhibit GSK-3β that normally regulates the proliferation and survival of pancreatic cancer cells [34], finally leading to attenuation of cancer progression [35]. Moreover, high IL-33 (50 ng/ml) inhibited the growth and promoted apoptosis in colorectal cancer [36] and pancreatic cancer [13].…”

Section: Discussionsupporting

confidence: 71%

High level of interleukin-33 in cancer cells and cancer-associated fibroblasts correlates with good prognosis and suppressed migration in cholangiocarcinoma

et al. 2020

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Interleukin 33 (IL-33) promotes cholangiocarcinoma (CCA) genesis in a mouse model, however, its function in human CCA has not been clearly understood. This study was aimed to investigate IL-33 level in CCA tissues and its clinicopathological correlations. The results revealed that IL-33 was found in both cancer cells and stromal cancer-associated fibroblast (CAFs) staining patterns which were divided into high (CH) and low level (CL) in cancer cells; and presence (FP) and absence (FA) in CAFs. Kaplan-Meier analysis showed that patients in the CL group were significantly correlated with a short 2-year survival time (P = 0.027). The CL/FP group had a shorter survival time compared to the other groups with statistical significance for 2-year (P = 0.030) and 5-year (P = 0.023) survivals. In contrast, CH/FP patients had significantly greater 2-year (P = 0.003) and 5-year (P = 0.003) survivals. Univariate and multivariate analysis confirmed that CL/FP was a significantly independent risk factor whereas CH/FP was a significant protective factor in CCA patients. High IL-33 expressing CCA cells had low migration, but they showed increased migration when IL-33 expression was knocked down. The low level of recombinant human IL-33 (rhIL-33) (0.002-2 ng/ml) could promote CCA cell migration, in contrast to the suppressive effect at a high dose (20-200 ng/ml). In conclusion, the combination of high IL-33 level in cancer cells and CAFs is a potentially good prognosis marker in CCA patients. The in vitro migration suppressive effect of IL-33 may be the potential mechanism supporting its role as a good prognostic marker in CCA patients. The obtained results strengthen IL-33 as a promising predictor and therapeutic target for CCA.

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Section: Discussionsupporting

confidence: 71%

High level of interleukin-33 in cancer cells and cancer-associated fibroblasts correlates with good prognosis and suppressed migration in cholangiocarcinoma

et al. 2020

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“…In contrast, RKO mice had diminished numbers of ADM and low-grade PanIN lesions (1 and 2), as well as a reduced incidence of high-grade PanIN-3 and invasive cancer (Figure 1C and D) compared to KC mice. Since GSK-3β has been shown to participate in the regulation of pancreatic cancer cell proliferation (23,27), we examined the proliferation of neoplastic ducts in KC and RKO mice. As shown in Figure 1E and F, we observed an accumulation of EdU + /CK19 + ductal cells within neoplastic areas in KC mice, which were dramatically reduced in RKO mice.…”

Section: Resultsmentioning

confidence: 99%

“…Glycogen synthase kinases, GSK-3α and GSK-3β, were originally identified as key enzymes regulating glycogen metabolism (17–19). However, accumulating evidence has suggested a role for these kinases in several human malignancies (20–22) and has identified them as therapeutic targets in pancreatic cancer (23). Significantly, GSK-3β is overexpressed in PDA and aberrant nuclear accumulation, as well as increased mRNA expression of GSK-3β, has been associated with high-grade tumors (24,25).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, our prior studies showed that mutant KRas increases GSK-3β gene expression in vivo and in vitro (26,27). However, the studies conducted so far to address the multifaceted role of GSK-3β in pancreatic cancer in vivo have mostly relied on loss-of-function approaches including knockout mice or GSK-3 inhibitors (23). The role of nuclear GSK-3β in pancreatic cancer progression in vivo , particularly as it pertains to PDA precursor lesion development, is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Nuclear GSK-3β and Oncogenic KRas Promote Expansion of Terminal Duct Cells and the Development of Intraductal Papillary Mucinous Neoplasm

Ding

Roeck

Zhang³

et al. 2020

Preprint

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Intraductal papillary mucinous neoplasm (IPMN) represents one type of pancreatic ductal adenocarcinoma (PDA) precursor lesion, however its cell-of-origin remains unclear. Here we describe a new mouse model in which pancreas-specific Cre activation of a nuclear glycogen synthase kinase-3beta; transgene is combined with oncogenic KRas (referred to as KNGC). KNGC mice show accumulation of neoplastic ductal cells at 4-weeks that progressively develop into IPMN with low-grade dysplasia in advanced age. RNA-sequencing identified expression of several terminal duct cell lineage genes including Agr2 and Aqp5. Interestingly, Aqp5, a water channel, was found to be required for the development of IPMN lesions in KNGC mice. Staining of human IPMN samples indicates that these preneoplastic lesions also arise from expansion of the terminal duct population. Altogether, these data highlight the utility of the KNGC model for understanding the biology of IPMN and potential utility in defining predictive biomarkers of IPMN to PDA development.

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“…Overexpression of the serine/threonine kinase, glycogen synthase kinase 3β (GSK-3β), has been associated with reduced survival in PDAC patients, via regulation of the ATR DDR pathway. Moreover, signalling of mutant Kras has been shown to increase GSK-3β expression, which ultimately aids the growth and survival of Kras-mutant tumours [81]. Promising preclinical findings led to the initiation of an ongoing phase I/II clinical trial exploring the small molecule inhibitor 9-ING-41 to inhibit GSK-3β (NCT03678883).…”

Section: Targeting Dna Damage Responsementioning

confidence: 99%

The State-of-the-Art of Phase II/III Clinical Trials for Targeted Pancreatic Cancer Therapies

García-Sampedro

Gaggia

Ney

et al. 2021

JCM

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Pancreatic cancer is a devastating disease with very poor prognosis. Currently, surgery followed by adjuvant chemotherapy represents the only curative option which, unfortunately, is only available for a small group of patients. The majority of pancreatic cancer cases are diagnosed at advanced or metastatic stage when surgical resection is not possible and treatment options are limited. Thus, novel and more effective therapeutic strategies are urgently needed. Molecular profiling together with targeted therapies against key hallmarks of pancreatic cancer appear as a promising approach that could overcome the limitations of conventional chemo- and radio-therapy. In this review, we focus on the latest personalised and multimodal targeted therapies currently undergoing phase II or III clinical trials. We discuss the most promising findings of agents targeting surface receptors, angiogenesis, DNA damage and cell cycle arrest, key signalling pathways, immunotherapies, and the tumour microenvironment.

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Glycogen synthase kinase-3β: a novel therapeutic target for pancreatic cancer

Cited by 28 publications

References 93 publications

High level of interleukin-33 in cancer cells and cancer-associated fibroblasts correlates with good prognosis and suppressed migration in cholangiocarcinoma

High level of interleukin-33 in cancer cells and cancer-associated fibroblasts correlates with good prognosis and suppressed migration in cholangiocarcinoma

Nuclear GSK-3β and Oncogenic KRas Promote Expansion of Terminal Duct Cells and the Development of Intraductal Papillary Mucinous Neoplasm

The State-of-the-Art of Phase II/III Clinical Trials for Targeted Pancreatic Cancer Therapies

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