The role of lncRNA MSC-AS1/miR-29b-3p axis-mediated CDK14 modulation in pancreatic cancer proliferation and Gemcitabine-induced apoptosis

Cancer stem cells (CSCs) are crucial regulators of tumor recurrence/progression. The maintenance of CSCs is dependent on aberrant activation of various pathways, including Hedgehog. Prevalent sialylations contribute to aggressiveness in CSCs. Here, we have addressed the role of sialylation in regulating stemness-like properties of pancreatic cancer sphere-forming cells (PCS) through modulation of the Hedgehog (Hh) pathway. The status of CD133/CD44/surface-sialylation was checked by flow cytometry and effects of Neu2 overexpression in PCS were compared using qPCR, immunoblotting, co-immunoprecipitation and also by colony-formation assays. The work was also validated in a xenograft model after Neu2 overexpression. Neu2 and Shh status in patient tissues were examined by immunohistochemistry. PCS showed higher Hh-pathway activity and sialylation with reduced cytosolic-sialidase (Neu2). Neu2 overexpression caused desialylation of Shh, thereby reducing Shh-Patched1 binding thus causing decreased Hh-pathway activity with lower expression of Snail/Slug/CyclinD1 leading to reduction of stemness-like properties. Neu2-overexpression also induced apoptosis in PCS. Additionally, Neu2-overexpressed PCS demonstrated lower mTORC2 formation and inhibitory-phosphorylation of Gsk3β, reflecting a close relationship with reduced Hh pathway. Moreover, both Neu2 and Rictor (a major component of mTORC2) co-transfection reduced stem cell markers and Hh-pathway activity in PCS. Neu2-overexpressed tumors showed reduction in tumor mass with downregulation of stem cell markers/Shh/mTOR and upregulation of Bax/Caspase8/Caspase3. Thus, we established that reduced sialylation by Neu2 overexpression leads to decreased stemness-like properties by desialylation of Shh, which impaired its association with Patched1 thereby inhibiting the Hh pathway. All these may be responsible for enhanced apoptosis in Neu2-overexpressed PCS.

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Role of the eIF4E binding protein 4E-BP1 in regulation of the sensitivity of human pancreatic cancer cells to TRAIL and celastrol-induced apoptosis

Biology of the Cell ◽

10.1111/boc.201300021 ◽

2013 ◽

Vol 105 (9) ◽

pp. 414-429 ◽

Cited By ~ 9

Author(s):

Reka Chakravarthy ◽

Michael J. Clemens ◽

Grisha Pirianov ◽

Nectarios Perdios ◽

Satvinder Mudan ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Binding Protein ◽

Human Pancreatic Cancer ◽

Pancreatic Cancer Cells ◽

Induced Apoptosis

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Restore of miR-541 resensitizes pancreatic cancer cells to gemcitabine-induced apoptosis through suppression of HAX-1

10.21203/rs.3.rs-41511/v1 ◽

2020 ◽

Author(s):

Hong Liu ◽

Xuemei Gan ◽

Jun Zhang ◽

Xingdiao Zhang ◽

Jie Xiong ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Luciferase Reporter ◽

Pancreatic Cancer Cells ◽

Reporter Assays ◽

Potential Strategy ◽

Induced Apoptosis ◽

Mtt Assays

Abstract Background: MiR-541 acts as a tumor suppressor in some cancers. However, the role of miR-541 in regulating the chemosensitivity to cancer cells is still unclear. The aim of this study is to explore the effect of miR-541 on chemoresistance of pancreatic cancer (PCa) cells to gemcitabine-induced apoptosis.Methods: Gemcitabine-resistant Panc-1 and Capan-2 PCa cell lines (Panc-1/R and Capan-2/R) were established through long term exposure to gemcitabine. Effect of miR-541 on changing the sensitivity of Panc-1/R and Capan-2/R to gemcitabine-induced cytotoxicity was evaluated by MTT assays. Regulation of miR-541 on HAX-1 was confirmed by bioinformatics, western blot analysis and luciferase reporter assays. Cell apoptosis and mitochondrial membrane potential (MMP) was measured by flow cytometry analysis.Results: Comparison with Panc-1 and Capan-2, downregulation of miR-541 was observed in Panc-1/R and Capan-2/R cells. Overexpression of miR-541 was found to increase the cytotoxicity of gemcitabine to Panc-1/R and Capan-2/R cells. However, transfection with HAX-1 plasmid can abolish the effect of miR-541 on gemcitabine-induced cytotoxicity against Panc-1/R and Capan-2/R.Conclusion: Downregulation of miR-541 is responsible for development of gemcitabine resistance in PCa. Overexpression of miR-541 may represent a potential strategy to reverse the chemoresistance of PCa.

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Pancreatic Cancer and Primary Sjögren’s Syndrome: A Case Report

Case Reports in Rheumatology ◽

10.1155/2021/9915881 ◽

2021 ◽

Vol 2021 ◽

pp. 1-5

Author(s):

Daniela Oliveira ◽

Vanessa Chaves ◽

José Carlos Martins ◽

Carlos Vaz ◽

Miguel Bernardes ◽

...

Keyword(s):

Pancreatic Cancer ◽

High Risk ◽

Systemic Autoimmune Disease ◽

Cancer Proliferation ◽

Hematological Cancer ◽

Active Smoker ◽

Primary Sjögren Syndrome ◽

Metastatic Pancreatic Adenocarcinoma ◽

Risk Of Malignancy

Primary Sjögren syndrome (SS) is a chronic inflammatory systemic autoimmune disease with a high risk of malignancy development, namely, lymphoproliferative neoplasms. Few studies also reported a high risk of solid cancers; however, the coexistence of primary SS and pancreatic cancer has been rarely described. In this paper, we aim to describe a case of a 59-year-old woman who was an active smoker with sicca symptoms and symmetrical polyarthritis and was diagnosed with primary SS two years before the development of metastatic pancreatic adenocarcinoma. Despite institution of chemotherapy, the patient succumbed to the malignancy. Besides that, we explore the link between primary SS and solid cancers including the main predictors of malignancy and the role of primary SS as a paraneoplastic syndrome. Patients with primary SS should be closely monitored for malignancy, not only for hematological cancer, but also for solid tumors. Further research is necessary to understand which are the predictors of cancer proliferation in primary SS patients.

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Triptolide to induce cell death of pancreatic cancer cells via inhibition of 14-3-3γ expression.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.425 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 425-425

Author(s):

Wei Wang ◽

Jinbing Luo ◽

Yinghui Liang ◽

Yubin Chen ◽

Wenjie Lin

Keyword(s):

Pancreatic Cancer ◽

Western Blot ◽

Cancer Cells ◽

Caspase 8 ◽

Down Regulation ◽

Pancreatic Cancer Cells ◽

Growth Inhibitory ◽

Induced Apoptosis

425 Background: Pancreatic cancer is one of the malignant tumors which exhibit resistance to chemotherapy. Gemcitabine-based therapy is a standard for advanced pancreatic cancer though it brings severe side-effect and average median survival is only 6 months. Hence increasing interest has focused on new agent with targeted therapies. Here we investigated the growth-inhibitory and apoptotic effect of triptolide, a diterpenoid triepoxide, and the role of 14-3-3γ expression in the apoptotic pathway induced by triptolide in human pancreatic cancer cells (AsPC-1 and PANC-1). Methods: Cell proliferation was measured by SRB, apoptotic cells were assessed by flow cytometry for Annexin V/PI staining and western blot for cleaved caspase-8, 9, 3 and fluorescent substrate assay for activities of caspase-8, 9, 3. To explore further mechanism of triptolide triggering death receptor pathway, specific siRNA targeted for 14-3-3γ was used to knock down 14-3-3γ expression measured by ELISA. In vivo, AsPC-1 xenografts in the absence or presence of stable down-regulation of 14-3-3γ expression by RNAi were treated with triptolide for 4 weeks and the tumor growth was compared, tumor samples were tested by ELISA and western blot for 14-3-3γ level. Results: Triptolide inhibits the proliferation at extremely low concentrations (12.5-50 nM) and induces apoptosis of pancreatic cancer cells through activating the caspase cascade associated with Bid cleavage. Moreover triptolide inhibited 14-3-3γ expression at dose and time-dependent manner and 14-3-3γ down-regulation sensitized cells to triptolide-induced apoptosis. Likewise, in vivo experiment of AsPC-1 xenografts, stable down-regulation of 14-3-3γ expression by RNAi significantly enhances triptolide-induced apoptosis and tumor growth delay. Conclusions: Triptolide exerted significant growth inhibitory effects and induced apoptosis in vitro and in vivo. Triptolide may have a potential to be an effective agent against pancreatic cancer and its mechanism of action is mediated by the inhibition of 14-3-3γ expression. The role of 14-3-3γ expression involved in resistance to apoptosis pathway make it be a potential therapeutic target in pancreatic cancer.

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