Aberrant glycogen synthase kinase 3β in the development of pancreatic cancer

Shimasaki, Takeo; Kitano, Ayako; Motoo, Yoshiharu; Minamoto, Toshinari

doi:10.4103/1477-3163.100866

Cited by 11 publications

(7 citation statements)

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“…We and others have shown that GSK-3 β is progressively overexpressed during progression from pancreatic intraepithelial neoplasia to advanced PDA and is localized to the nucleus in most moderately and poorly differentiated tumors. 23 , 24 , 25 , 26 Additionally, it has been observed that GSK-3 β overexpression contributes to PDA cell proliferation and survival, whereas GSK-3 inhibition reduces pancreatic cancer cell viability in vitro and suppresses tumor xenograft growth in vivo , at least partly, via downregulation of NF- κ B activity. 23 , 24 , 25 , 26 , 27 , 28 In view of the impact of NF- κ B target genes on TRAIL-induced apoptosis, we have assessed the impact of GSK-3 inhibition or downregulation on TRAIL-induced killing and have examined the mechanism of GSK-3 inhibitor (GSK-3i)-mediated TRAIL sensitization in PDA cells.…”

mentioning

confidence: 99%

Differential activity of GSK-3 isoforms regulates NF-κB and TRAIL- or TNFα induced apoptosis in pancreatic cancer cells

Herreros-Villanueva

Köenig

et al. 2014

Cell Death Dis

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While TRAIL is a promising anticancer agent due to its ability to selectively induce apoptosis in neoplastic cells, many tumors, including pancreatic ductal adenocarcinoma (PDA), display intrinsic resistance, highlighting the need for TRAIL-sensitizing agents. Here we report that TRAIL-induced apoptosis in PDA cell lines is enhanced by pharmacological inhibition of glycogen synthase kinase-3 (GSK-3) or by shRNA-mediated depletion of either GSK-3α or GSK-3β. In contrast, depletion of GSK-3β, but not GSK-3α, sensitized PDA cell lines to TNFα-induced cell death. Further experiments demonstrated that TNFα-stimulated IκBα phosphorylation and degradation as well as p65 nuclear translocation were normal in GSK-3β-deficient MEFs. Nonetheless, inhibition of GSK-3β function in MEFs or PDA cell lines impaired the expression of the NF-κB target genes Bcl-xL and cIAP2, but not IκBα. Significantly, the expression of Bcl-xL and cIAP2 could be reestablished by expression of GSK-3β targeted to the nucleus but not GSK-3β targeted to the cytoplasm, suggesting that GSK-3β regulates NF-κB function within the nucleus. Consistent with this notion, chromatin immunoprecipitation demonstrated that GSK-3 inhibition resulted in either decreased p65 binding to the promoter of BIR3, which encodes cIAP2, or increased p50 binding as well as recruitment of SIRT1 and HDAC3 to the promoter of BCL2L1, which encodes Bcl-xL. Importantly, depletion of Bcl-xL but not cIAP2, mimicked the sensitizing effect of GSK-3 inhibition on TRAIL-induced apoptosis, whereas Bcl-xL overexpression ameliorated the sensitization by GSK-3 inhibition. These results not only suggest that GSK-3β overexpression and nuclear localization contribute to TNFα and TRAIL resistance via anti-apoptotic NF-κB genes such as Bcl-xL, but also provide a rationale for further exploration of GSK-3 inhibitors combined with TRAIL for the treatment of PDA.

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confidence: 99%

Differential activity of GSK-3 isoforms regulates NF-κB and TRAIL- or TNFα induced apoptosis in pancreatic cancer cells

Herreros-Villanueva

Köenig

et al. 2014

Cell Death Dis

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“…However, GSK-3β itself plays different roles in different cases. Previous studies have shown that GSK-3β overexpression plays key roles in multiple types of cancer, including ovarian cancer [ 22 ], breast cancer [ 23 ], pancreatic cancer [ 24 – 26 ], colon cancer [ 27 ], bladder cancer [ 28 ], myeloma [ 29 ] and leukaemia [ 30 ]. Sun et al reported that GSK-3β controls PCa cell autophagy and that GSK-3β inhibition triggers autophagy [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

ST6Gal-I overexpression facilitates prostate cancer progression via the PI3K/Akt/GSK-3β/β-catenin signaling pathway

et al. 2016

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ST6Gal-I sialyltransferase adds α2,6-linked sialic acids to the terminal ends of glycan chains of glycoproteins and glycolipids. ST6Gal-I is reportedly upregulated in many cancers, including hepatocellular carcinoma, ovarian cancer and breast cancer. However, the expression and function of ST6Gal-I in prostate cancer (PCa) and the mechanism underlying this function remain largely unknown. In this study, we observed that ST6Gal-I expression was upregulated in human PCa tissues compared to non-malignant prostate tissues. High ST6Gal-I expression was positively correlated with Gleason scores, seminal vesicle involvement and poor survival in patients with PCa. ST6Gal-I knockdown in aggressive prostate cancer PC-3 and DU145 cells significantly inhibited the proliferation, growth, migration and invasion capabilities of these cells. ST6Gal-I knockdown decreased the levels of several PI3K/Akt/GSK-3β/ β-catenin pathway components, such as p-PI3K, (Ser473)p-Akt, (Ser9)p-GSK-3β and β-catenin. Furthermore, targeting this pathway with a PI3K inhibitor or Akt RNA interference decreased p-Akt, p-GSK-3β and β-catenin expression, resulting in decreased PC-3 and DU145 proliferation, migration and invasion. Taken together, these results indicate that ST6Gal-I plays a critical role in cell proliferation and invasion via the PI3K/Akt/GSK-3β/β-catenin signaling pathway during PCa progression and that it might be a promising target for PCa prognosis determination and therapy.

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“…The majority of these studies have also demonstrated therapeutic effects against the respective cancer types using various pharmacological GSK3β inhibitors including lithium, natural products and medicines with GSK3β-inhibiting activity, and GSK3β-specific short interfering (si) or short hairpin (sh)RNA that are highly selective for GSK3β inhibition. The most extensively investigated cancer types to date are colon and rectum [ 161 ], pancreas [ 162 , 163 , 164 , 165 ] and prostate [ 166 ], as well as glioblastoma [ 167 , 168 , 169 ] and leukemia [ 170 , 171 , 172 ]. Compared to GSK3β, only a few studies have investigated the tumor-promoting role of GSK3α, another isoform of the GSK3 family, in pancreatic cancer and acute myeloid leukemia [ 173 , 174 , 175 ].…”

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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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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Aberrant glycogen synthase kinase 3β in the development of pancreatic cancer

Cited by 11 publications

References 100 publications

Differential activity of GSK-3 isoforms regulates NF-κB and TRAIL- or TNFα induced apoptosis in pancreatic cancer cells

Differential activity of GSK-3 isoforms regulates NF-κB and TRAIL- or TNFα induced apoptosis in pancreatic cancer cells

ST6Gal-I overexpression facilitates prostate cancer progression via the PI3K/Akt/GSK-3β/β-catenin signaling pathway

Glycogen Synthase Kinase 3β in Cancer Biology and Treatment

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