ShRNA silencing glycogen synthase kinase-3 beta inhibits tumor growth and angiogenesis in pancreatic cancer

Zhou, Wei; Wang, Li; Gou, Shanmiao; Wang, Tongling; Zhang, Meng; Liu, Tao; Wang, Chunyou

doi:10.1016/j.canlet.2011.10.033

Cited by 50 publications

(33 citation statements)

References 38 publications

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“…Also in HUVECs, the inhibition of Akt/GSK3b and mTOR signaling led to a suppression of angiogenesis in vitro and in vivo (33). Furthermore, in silencing experiments, Zhou and colleagues demonstrated that the elimination of GSK3b inhibited tumor growth and angiogenesis in a pancreatic cancer model (34). Concordantly, we demonstrated that both moguntinones reduce the mTOR signaling in HT-29 (Fig.…”

Section: Resultssupporting

confidence: 65%

Moguntinones—New Selective Inhibitors for the Treatment of Human Colorectal Cancer

Maderer

Plutizki

Kramb

et al. 2014

Molecular Cancer Therapeutics

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3-Indolyl and 3-azaindolyl-4-aryl maleimide derivatives, called moguntinones (MOG), have been selected for their ability to inhibit protein kinases associated with angiogenesis and induce apoptosis. Here, we characterize their mode of action and their potential clinical value in human colorectal cancer in vitro and in vivo. MOG-19 and MOG-13 were characterized in vitro using kinase, viability, and apoptosis assays in different human colon cancer (HT-29, HCT-116, Caco-2, and SW480) and normal colon cell lines (CCD-18Co, FHC, and HCoEpiC) alone or in combination with topoisomerase I inhibitors. Intracellular signaling pathways were analyzed by Western blotting. To determine their potential to inhibit tumor growth in vivo, the human HT-29 tumor xenograft model was used. Moguntinones prominently inhibit several protein kinases associated with tumor growth and metastasis. Specific signaling pathways such as GSK3b and mTOR downstream targets were inhibited with IC 50 values in the nanomolar range. GSK3b signaling inhibition was independent of KRAS, BRAF, and PI3KCA mutation status. While moguntinones alone induced apoptosis only in concentrations >10 mmol/L, MOG-19 in combination with topoisomerase I inhibitors induced apoptosis synergistically at lower concentrations. Consistent with in vitro data, MOG-19 significantly reduced tumor volume and weight in combination with a topoisomerase I inhibitor in vivo. Our in vitro and in vivo data present significant proapoptotic, antiangiogenic, and antiproliferative effects of MOG-19 in different human colon cancer cells. Combination with clinically relevant topoisomerase I inhibitors in vitro and xenograft mouse model demonstrate a high potency of moguntinones to complement and improve standard chemotherapy options in human colorectal cancer. Mol Cancer Ther; 13(6); 1399-409. Ó2014 AACR.

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Section: Resultssupporting

confidence: 65%

Moguntinones—New Selective Inhibitors for the Treatment of Human Colorectal Cancer

Maderer

Plutizki

Kramb

et al. 2014

Molecular Cancer Therapeutics

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“…Wnt5a RNA Interference-Scrambled (Scr) shRNA and Wnt5a-shRNA HDPCs were generated and maintained as described previously (45). An oligoribonucleotide with the following sequence was used: 5Ј-CCGGCCCTGTTCAGATG-TCAGAATTCAAGAGATTCTGACATCTGAACAGGGTT-TTTTG-3Ј.…”

Section: Construction Of a Dental Pulp Inflammatory Model In Rats-mentioning

confidence: 99%

Wnt5a Promotes Inflammatory Responses via Nuclear Factor κB (NF-κB) and Mitogen-activated Protein Kinase (MAPK) Pathways in Human Dental Pulp Cells

Zhao

Wang

et al. 2014

Journal of Biological Chemistry

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Background: Wnt5a is involved in inflammation.Results: Wnt5a promotes an inflammatory response by up-regulating chemokines and cytokines via the NF-B and MAPK pathways in HDPCs, leading to macrophage migration. Conclusion: Wnt5a, as an inflammatory mediator, drives the integration of cytokines and chemokines to control dental pulp inflammation. Significance: Wnt5a-mediated inflammation occurs downstream of TNF-␣.

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“…Suppression of GSK-3beta expression inhibited pancreatic cancer growth and angiogenesis [125]. Decreased levels of Bcl-2 and vascular endothelial growth factor (VEGF) were detected in cells which had GSK-3beta knocked-down.…”

Section: Gsk-3 As a Tumor-promotermentioning

confidence: 99%

GSK-3 as potential target for therapeutic intervention in cancer

et al. 2014

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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.

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ShRNA silencing glycogen synthase kinase-3 beta inhibits tumor growth and angiogenesis in pancreatic cancer

Cited by 50 publications

References 38 publications

Moguntinones—New Selective Inhibitors for the Treatment of Human Colorectal Cancer

Moguntinones—New Selective Inhibitors for the Treatment of Human Colorectal Cancer

Wnt5a Promotes Inflammatory Responses via Nuclear Factor κB (NF-κB) and Mitogen-activated Protein Kinase (MAPK) Pathways in Human Dental Pulp Cells

GSK-3 as potential target for therapeutic intervention in cancer

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