Primary and Liver Metastasis–Derived Cell Lines From KrasG12D; Trp53R172H; Pdx-1 Cre Animals Undergo Apoptosis in Response to Triptolide

Sangwan, Veena; Banerjee, Sulagna; Jensen, Kelsey; Chen, Zhiyu; Chugh, Rohit; Dudeja, Vikas; Vickers, Selwyn M.; Saluja, Ashok K.

doi:10.1097/mpa.0000000000000317

Cited by 21 publications

(14 citation statements)

References 32 publications

(41 reference statements)

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“…Metastasis is the ultimate cause of death for most cancer patients. TP has been reported as an inhibitor of lung cancer cell migration and metastasis, but its mechanism is not clearly defined [12,57,58]. We observed some other differentially expressed proteins, such as MTA2 and E-cadherin (CDH1), implicated in cancer cell migration.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 69%

ITRAQ-Based Proteomics Analysis of Triptolide On Human A549 Lung Adenocarcinoma Cells

Zhao

Yang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Triptolide (TP) is a diterpenoid triepoxide extracted from the traditional Chinese medical herb Tripterygium wilfordii that exerts prominent broad-spectrum anticancer activity to repress proliferation and induce cancer cell apoptosis through various molecular pathways. We previously observed that TP inhibits the progression of A549 cells and pancreatic cancer cells (PNCA-1) in vitro. However, the complex molecular mechanism underlying the anticancer activity of TP is not well understood. Methods: To explore the molecular mechanisms by which TP induces lung cancer cell apoptosis, we investigated changes in the protein profile of A549 cells treated with TP using a proteomics approach (iTRAQ [isobaric tags for relative and absolute quantitation] combined with NanoLC-MS/MS [nano liquid chromatographymass spectrometry]). Changes in the profiles of the expressed proteins were analyzed using the bioinformatics tools OmicsBean and the Kyoto Encyclopedia of Genes and Genomes (KEGG) and were verified using western blotting. Apoptosis and cell cycle effects were analyzed using flow cytometry. Results: TP induced apoptosis in A549 cells and blocked A549 cells at the G2/M phase. Using iTRAQ technology, we observed 312 differentially expressed proteins associated in networks and implicated in different KEGG pathways. Gene Ontology (GO) analysis showed the overviews of dysregulated proteins in the biological process (BP), cell component (CC), and molecular function (MF) categories. Moreover, some candidate proteins involved in PARP1/AIF and nuclear Akt signaling pathways or metastasis processes were validated by western blotting. Conclusion: TP exerted anti-tumor activity on non-small cell lung cancer (NSCLC) A549 lung adenocarcinoma cells by dysregulating tumor-related protein expression. Herein, we provide a preliminary study of TP-related cytotoxicity on A549 cells using proteomics tools. These findings may improve the current understanding of the anti-tumor effects of TP on lung cancer cells and may reveal candidate proteins as potential targets for the treatment of lung cancer.

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Section: Cellular Physiology and Biochemistrymentioning

confidence: 69%

ITRAQ-Based Proteomics Analysis of Triptolide On Human A549 Lung Adenocarcinoma Cells

Zhao

Yang

et al. 2018

Cell Physiol Biochem

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“…The TECs were isolated according to our previous study(22). Isolation of CAFs (CAF-1, CAF-5 and CAF-7) from three KPC mice was performed following the protocol described by Sharon et al(26).…”

Section: Methodsmentioning

confidence: 99%

“…For ease of clinical application, we have developed a water-soluble prodrug, Minnelide for this compound (17–22). Mechanistically, we have demonstrated that Minnelide downregulates HSP70 via inhibition of the activity of the transcription factor Sp1, thereby leading to pancreatic cancer cell death(23,24).…”

Section: Introductionmentioning

confidence: 99%

Inactivation of Cancer-Associated-Fibroblasts Disrupts Oncogenic Signaling in Pancreatic Cancer Cells and Promotes Its Regression

et al. 2018

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Resident fibroblasts that contact tumor epithelial cells (TEC) can become irreversibly activated as cancer-associated-fibroblasts (CAF) which stimulate oncogenic signaling in TEC. In this study, we evaluated the crosstalk between CAF and TEC isolated from tumors generated in a mouse model of KRAS/mutp53-induced pancreatic cancer (KPC mice). Transcriptomic profiling conducted after treatment with the anticancer compound Minnelide revealed deregulation of the TGF-β signaling pathway in CAF, resulting in an apparent reversal of their activated state to a quiescent, non-proliferative state. TEC exposed to media conditioned by drug-treated CAF exhibited a decrease in oncogenic signaling as manifested by downregulation of the transcription factor Sp1. This inhibition was rescued by treating TEC with TGF-β. Given promising early clinical studies with Minnelide, our findings suggest that approaches to inactivate CAF and prevent tumor-stroma crosstalk may offer a viable strategy to treat pancreatic cancer.

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“…10 For animal experiments, KPC cell lines were trypsinized and resuspended in phosphate buffered saline/Matrigel in a 1:1 ratio. C57BL/6J mice were anesthetized, laparotomy was performed, and 50,000 cells were injected into the tail of the pancreas.…”

Section: Methodsmentioning

confidence: 99%

A Novel Immunocompetent Mouse Model of Pancreatic Cancer with Robust Stroma: a Valuable Tool for Preclinical Evaluation of New Therapies

Majumder

Arora

Modi

et al. 2016

Journal of Gastrointestinal Surgery

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A valid preclinical tumor model should recapitulate the tumor microenvironment. Immune and stromal components are absent in immunodeficient models of pancreatic cancer. While these components are present in genetically engineered models such as KrasG12D; Trp53R172H; Pdx-1Cre (KPC), immense variability in development of invasive disease makes them unsuitable for evaluation of novel therapies. We have generated a novel mouse model of pancreatic cancer by implanting tumor fragments from KPC mice into the pancreas of wild type mice. Three-millimeter tumor pieces from KPC mice were implanted into the pancreas of C57BL/6J mice. Four to eight weeks later, tumors were harvested, and stromal and immune components were evaluated. The efficacy of Minnelide, a novel compound which has been shown to be effective against pancreatic cancer in a number of preclinical murine models, was evaluated. In our model, consistent tumor growth and metastases were observed. Tumors demonstrated intense desmoplasia and leukocytic infiltration which was comparable to that in the genetically engineered KPC model and significantly more than that observed in KPC tumor-derived cell line implantation model. Minnelide treatment resulted in a significant decrease in the tumor weight and volume. This novel model demonstrates a consistent growth rate and tumor-associated mortality and recapitulates the tumor microenvironment. This convenient model is a valuable tool to evaluate novel therapies.

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Primary and Liver Metastasis–Derived Cell Lines From KrasG12D; Trp53R172H; Pdx-1 Cre Animals Undergo Apoptosis in Response to Triptolide

Cited by 21 publications

References 32 publications

ITRAQ-Based Proteomics Analysis of Triptolide On Human A549 Lung Adenocarcinoma Cells

ITRAQ-Based Proteomics Analysis of Triptolide On Human A549 Lung Adenocarcinoma Cells

Inactivation of Cancer-Associated-Fibroblasts Disrupts Oncogenic Signaling in Pancreatic Cancer Cells and Promotes Its Regression

A Novel Immunocompetent Mouse Model of Pancreatic Cancer with Robust Stroma: a Valuable Tool for Preclinical Evaluation of New Therapies

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