p21-Activated kinase 3 promotes cancer stem cell phenotypes through activating the Akt-GSK3β-β-catenin signaling pathway in pancreatic cancer cells

Wu, Hai; Yang, Ming-Chen; Ding, Liang; Chen, Ching-Shiun; Chu, Po-Chen

doi:10.1016/j.canlet.2019.04.026

Cited by 20 publications

(18 citation statements)

References 46 publications

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“…[28][29][30] Our results suggest that imperatorin promotes phosphorylation of AKT ( Figure 2E). [28][29][30] Our results suggest that imperatorin promotes phosphorylation of AKT ( Figure 2E).…”

Section: However During Osteogenic Induction the Phosphorylation Ofmentioning

confidence: 61%

“…Studies have shown that AKT acts as an upstream signal to regulate the AKT/GSK3β/β-catenin signal axis. [28][29][30] Our results suggest that imperatorin promotes phosphorylation of AKT ( Figure 2E). To verify that AKT plays an essential role in imperatorin promoting osteogenesis, we selected ipatasertib (IPATA; Selleck), a novel, highly selective, pan-AKT inhibitor.…”

Section: However During Osteogenic Induction the Phosphorylation Ofmentioning

confidence: 61%

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Imperatorin promotes osteogenesis and suppresses osteoclast by activating AKT/GSK3 β/β‐catenin pathways

Yan

Tang

Chen

et al. 2019

J Cellular Molecular Medi

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Osteoporosis is caused by disturbance in the dynamic balance of bone remodelling, a physiological process, vital for maintenance of healthy bone tissue in adult humans. In this process, a new bone is formed by osteoblasts and the pre‐existing bone matrix is resorbed by osteoclasts. Imperatorin, a widely available and inexpensive plant extract with antioxidative and apoptotic effects, is reported to treat osteoporosis. However, the underlying mechanism and specific effects on bone metabolism have not been elucidated. In this study, we used rat bone marrow‐derived mesenchymal stem cells and found that imperatorin can activate RUNX2, COL1A1 and osteocalcin by promoting the Ser9 phosphorylation of GSK3β and entry of β‐catenin into the nucleus. Imperatorin also enhanced the production of phospho‐AKT (Ser473), an upstream factor that promotes the Ser9 phosphorylation of GSK3β. We used ipatasertib, a pan‐AKT inhibitor, to inhibit the osteogenic effect of imperatorin, and found that imperatorin promotes osteogenesis via AKT/GSK3β/β‐catenin pathway. Next, we used rat bone marrow‐derived monocytes, to check whether imperatorin inhibits osteoclast differentiation via AKT/GSK3β/β‐catenin pathway. Further, we removed the bilateral ovaries of rats to establish an osteoporotic model. Intragastric administration of imperatorin promoted osteogenesis and inhibited osteoclast in vivo. Our experiments showed that imperatorin is a potential drug for osteoporosis treatment.

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Section: However During Osteogenic Induction the Phosphorylation Ofmentioning

confidence: 61%

Section: However During Osteogenic Induction the Phosphorylation Ofmentioning

confidence: 61%

Imperatorin promotes osteogenesis and suppresses osteoclast by activating AKT/GSK3 β/β‐catenin pathways

Yan

Tang

Chen

et al. 2019

J Cellular Molecular Medi

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“…The dual role of p21 in cancer progression as an oncogene and tumor suppressor [16,148] makes it harder to have one approach for all cancer types; nevertheless, according to the literature, we believe that p21 induction has a synergic effect on other treatments, as it has been shown for several combination therapies, mentioned in this review [149]. On the other hand, looking at studies on cancer stem cells, one could agree that p21 plays an important role in inducing stemness, especially through p21 activated kinases (PAK1, PAK3, and PAK4) [143,144,145,146]. lincRNA-p21, on the other hand, suppresses stem cell expansion and renewal [140,141].…”

Section: Discussionmentioning

confidence: 79%

“…p21-activated kinase 3 (PAK3) controls Akt-GSK3β (Glycogen Synthase Kinase 3 beta)-β-catenin signaling in pancreatic cancer cells. PAK3 inhibition leads to suppressed tumorigenesis and CSCs expansion [143]. PAK1 was shown to upregulate CSC markers and cause resistance to 5-fluorouracil (5-FU) chemotherapy, leading to colorectal cancer progression [144].…”

Section: P21 Role In Stemnessmentioning

confidence: 99%

p21 in Cancer Research

Shamloo

Usluer

2019

Cancers

252

139

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p21 functions as a cell cycle inhibitor and anti-proliferative effector in normal cells, and is dysregulated in some cancers. Earlier observations on p21 knockout models emphasized the role of this protein in cell cycle arrest under the p53 transcription factor activity. Although tumor-suppressor function of p21 is the most studied aspect of this protein in cancer, the role of p21 in phenotypic plasticity and its oncogenic/anti-apoptotic function, depending on p21 subcellular localization and p53 status, have been under scrutiny recently. Basic science and translational studies use precision gene editing to manipulate p21 itself, and proteins that interact with it; these studies have led to regulatory/functional/drug sensitivity discoveries as well as therapeutic approaches in cancer field. In this review, we will focus on targeting p21 in cancer research and its potential in providing novel therapies.

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“…PAK4 maintains cancer stem cell phenotypes through Stat3 signaling [21]. PAK3 promotes CSC phenotypes through Akt-GSK3β-β-catenin signaling in pancreatic cancers [22].…”

Section: Introductionmentioning

confidence: 99%

The PAK1-Stat3 Signaling Pathway Activates IL-6 Gene Transcription and Human Breast Cancer Stem Cell Formation

Kim

Choi

Kim

et al. 2019

Cancers

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Cancer stem cells (CSCs) have unique properties, including self-renewal, differentiation, and chemoresistance. In this study, we found that p21-activated kinase (PAK1) inhibitor (Group I, PAK inhibitor, IPA-3) and inactivator (ivermectin) treatments inhibit cell proliferation and that tumor growth of PAK1-knockout cells in a mouse model is significantly reduced. IPA-3 and ivermectin inhibit CSC formation. PAK1 physically interacts with Janus Kinase 2 (JAK2), and JAK2 inhibitor (TG101209) treatment inhibits mammosphere formation and reduces the nuclear PAK1 protein level. PAK1 interacts with signal transducer and activator of transcription 3 (Stat3), and PAK1 and Stat3 colocalize in the nucleus. We show through electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), and reporter assays that the PAK1/Stat3 complex binds to the IL-6 promoter and regulates the transcription of the IL-6 gene. Inhibition of PAK1 and JAK2 in mammospheres reduces the nuclear pStat3 and extracellular IL-6 levels. PAK1 inactivation inhibits CSC formation by decreasing pStat3 and extracellular IL-6 levels. Our results reveal that JAK2/PAK1 dysregulation inhibits the Stat3 signaling pathway and CSC formation, the PAK1/Stat3 complex regulates IL-6 gene expression, PAK1/Stat3 signaling regulates CSC formation, and PAK1 may be an important target for treating breast cancer.

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p21-Activated kinase 3 promotes cancer stem cell phenotypes through activating the Akt-GSK3β-β-catenin signaling pathway in pancreatic cancer cells

Cited by 20 publications

References 46 publications

Imperatorin promotes osteogenesis and suppresses osteoclast by activating AKT/GSK3 β/β‐catenin pathways

Imperatorin promotes osteogenesis and suppresses osteoclast by activating AKT/GSK3 β/β‐catenin pathways

p21 in Cancer Research

The PAK1-Stat3 Signaling Pathway Activates IL-6 Gene Transcription and Human Breast Cancer Stem Cell Formation

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