OSU-A9 inhibits pancreatic cancer cell lines by modulating p38-JAK-STAT3 signaling

Tsai, Wen Chun; Li, Bai; Chen, Yi Jin; Chu, Pei Ming; Hsu, Yu Wen; Sargeant, Aaron M.; Weng, Jing Ru

doi:10.18632/oncotarget.16450

Cited by 8 publications

(7 citation statements)

References 57 publications

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“…Src can increase pro-inflammatory cytokines production for tumor development and activate survival effectors for chemoresistance ( Su et al, 2014 ; Tsai et al, 2017 ), including TNF-α, IL-1β, IL6, phosphoinositide 3-kinases (PI3Ks), AKT and STAT3. Dasatinib has been shown to inhibit the growth of TNBC cell lines in vitro when used in combination with standard chemotherapy, such as cisplatin, or when used as a single agent ( Finn et al, 2007 ).…”

Section: Discussionmentioning

confidence: 99%

Kinome-Wide siRNA Screening Identifies Src-Enhanced Resistance of Chemotherapeutic Drugs in Triple-Negative Breast Cancer Cells

Tzeng

Liu

et al. 2018

Front. Pharmacol.

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Background: Chemotherapy is the main treatment for triple-negative breast cancer (TNBC), which lack molecular markers for diagnosis and therapy. Cancer cells activate chemoresistant pathways and lead to therapeutic failure for patients with TNBC. Several kinases have been identified as chemoresistant genes. However, the involvement of kinases in the chemoresistance in TNBC cells is not fully understood.Methods: We employed a kinome siRNA library to screen whether targeting any kinases could increase the chemosensitivity of TNBC cell lines. The effects of kinase on cell viability in various breast cancer cells were validated with ATP level and colony formation. Protein expression and phosphorylation were determined by immunoblotting. The Cancer Genome Atlas (TCGA) dataset was collected to analyze the correlation of Src expression with prognosis of TNBC patients.Results: Primary screening and validation for the initial hits showed that Src kinase was a potential doxorubicin-resistant kinase in the TNBC cell lines MDA-MB-231 and Hs578T. Both siRNA against Src and the Src inhibitor dasatinib enhanced the cytotoxic effects of doxorubicin in TNBC cells. Moreover, phosphorylation of AKT and signal transducer and activator of transcription 3 (STAT3), downstream effectors of Src, were accordingly decreased in Src-silenced or -inhibited TNBC cells. Additionally, TCGA data analysis indicated that Src expression levels in tumor tissues were higher than those in tumor-adjacent normal tissues in patients with TNBC. High co-expression level of Src and STAT3 was also significantly correlated with poor prognosis in patients.Conclusion: Our results showed that Src-STAT3 axis might be involved in chemoresistance of TNBC cells.

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Section: Discussionmentioning

confidence: 99%

Kinome-Wide siRNA Screening Identifies Src-Enhanced Resistance of Chemotherapeutic Drugs in Triple-Negative Breast Cancer Cells

Tzeng

Liu

et al. 2018

Front. Pharmacol.

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“…JNK is activated by environmental and toxic stresses and is important in inflammation through the control of cell proliferation, differentiation, survival and migration of various cell types (16). p38 is activated by cell stress-induced signalling in response to various factors including toxic chemicals and oxidative stress (17). STAT3 activation also leads to increased cell proliferation, angiogenesis, multidrug resistance and decreased cell apoptosis (18).…”

Section: Discussionmentioning

confidence: 99%

“…The activity of Akt is also regulated by casein kinase 2 (CK2) inhibitor (12). Mitogen-activated protein kinase (MAPK) signalling pathways relay and integrate signals from a wide range of stimuli and control cellular proliferation, cell cycle and apoptosis (13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Quinalizarin exerts an anti-tumour effect on lung cancer A549 cells by modulating the Akt, MAPK, STAT3 and p53 signalling pathways

Liu

Luo

et al. 2017

Mol Med Report

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Quinalizarin may be a potential chemical agent for cancer therapy, as it exerts anti‑tumour effects against a variety of different types of cancer. However, the underlying regulatory mechanism and signalling pathways of quinalizarin in lung cancer cells remains unknown. The present study sought to investigate the effects of quinalizarin on proliferation, apoptosis and reactive oxygen species (ROS) generation in lung cancer. MTT assays were used to evaluate the effects of quinalizarin on the viability of lung cancer A549, NCI‑H460 and NCI‑H23 cells. Flow cytometry was employed to evaluate the effects of quinalizarin on the cell cycle, apoptosis and ROS generation in A549 cells. Western blotting was performed to detect cell cycle and apoptosis‑associated protein expression levels in A549 cells. Quinalizarin inhibited A549, NCI‑H460 and NCI‑H23 cell proliferation and induced A549 cell cycle arrest at the G0/G1 phase. Quinalizarin induced apoptosis by upregulating the expression of B‑cell lymphoma 2 (Bcl‑2)‑associated agonist of cell death, cleaved‑caspase‑3 and cleaved‑poly (adenosine diphosphate‑ribose) polymerase, and downregulating the expression of Bcl‑2. Furthermore, quinalizarin activated mitogen‑activated protein kinase (MAPK) and p53, and inhibited the protein kinase B and signal transducer and activator of transcription‑3 (STAT3) signalling pathways. In addition, quinalizarin increased ROS generation. The ROS scavenger N‑acetyl‑L‑cysteine restored quinalizarin‑induced cell apoptosis, and inactivated the MAPK and STAT3 signalling pathways. The results of the present study demonstrated that quinalizarin induces G0/G1 phase cell cycle arrest and apoptosis via ROS mediated‑MAPK and STAT3 signalling pathways.

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“…In response to a variety of cytokines or related factors (e.g., interferon, interleukins), JAK2 protein is activated via phosphorylation at two adjacent tyrosine residues and then phosphorylates and activates cytoplasmic STAT3 protein. Activated STAT3 can transfer into the nucleus and bind specific regulatory sequences to either activate or suppress transcription of target genes like c-Myc and cyclin D1 [ 6 – 9 ]. As a result, activated STAT3 plays a crucial role in regulating the cell cycle, apoptosis, and angiogenesis [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

The anti-dysenteric drug fraxetin enhances anti-tumor efficacy of gemcitabine and suppresses pancreatic cancer development by antagonizing STAT3 activation

Guo

Xiao

Guo

et al. 2021

Aging

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Fraxetin, a natural product isolated and purified from the bark of Fraxinus bungeana A.DC. , has anti-inflammatory, analgesic, and anti-dysenteric activities. This study aimed to investigate the anti-tumor effects of fraxetin in pancreatic ductal adenocarcinoma (PDA). The effects of fraxetin on the malignant biological behavior of PDA were evaluated. Besides, the effects of fraxetin on the sensitivity of PCCs to gemcitabine, angiogenesis, the epithelial-mesenchymal transition (EMT), glucose metabolism, reactive oxygen species (ROS), and STAT3 activity were analyzed. By reversing the EMT, fraxetin suppressed proliferation, invasion, and migration, and induced mitochondrial-dependent apoptosis in PCCs. Also, treatment with fraxetin inhibited PDA growth and metastasis in nude mouse models. Furthermore, fraxetin made PCCs more sensitive to the chemotherapy drug gemcitabine. Mechanically, fraxetin treatment suppressed oncogenic KRAS-triggered STAT3 activation in PCCs and PDA tissues. Fraxetin shows significant interactions with STAT3 Src Homology 2 (SH2) domain residues, thereby preventing its homo-dimer formation, which then blocks the activation of downstream signal pathways. The anti-tumor activity of fraxetin in PDA was functionally rescued by a STAT3 activator colivelin. As a result, fraxetin hindered hypoxia-induced angiogenesis by decreasing HIF-1α and VEGFA expression, controlled glucose metabolism by reducing GLUT1 expression, inhibited the EMT by blocking the Slug-E-cadherin axis, and drove ROS-mediated apoptosis by regulating the STAT3-Ref1 axis. In conclusion, fraxetin enhances the anti-tumor activity of gemcitabine and suppresses pancreatic cancer development by antagonizing STAT3 activation.

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OSU-A9 inhibits pancreatic cancer cell lines by modulating p38-JAK-STAT3 signaling

Cited by 8 publications

References 57 publications

Kinome-Wide siRNA Screening Identifies Src-Enhanced Resistance of Chemotherapeutic Drugs in Triple-Negative Breast Cancer Cells

Kinome-Wide siRNA Screening Identifies Src-Enhanced Resistance of Chemotherapeutic Drugs in Triple-Negative Breast Cancer Cells

Quinalizarin exerts an anti-tumour effect on lung cancer A549 cells by modulating the Akt, MAPK, STAT3 and p53 signalling pathways

The anti-dysenteric drug fraxetin enhances anti-tumor efficacy of gemcitabine and suppresses pancreatic cancer development by antagonizing STAT3 activation

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