Targeting the C-MET/HGF Signaling Pathway in Pancreatic Ductal Adenocarcinoma

Ghanaatgar-Kasbi, Sadaf; Khorrami, Shadi; Avan, Amir; Aledavoud, Seyed A; Ferns, Gordon A.

doi:10.2174/1381612825666190110145855

Cited by 12 publications

(7 citation statements)

References 81 publications

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“…To further confirm whether hUC-MSC-enhanced autophagy was mediated by the secretion of HGF, the effect of tivantinib, a competitive inhibitor of HGF ( 24 ), in HK-2 cells was investigated. HK-2 cells were cultured with 0.0003, 0.0200, 0.1150, 0.2100, 0.3050 and 0.4000 µM tivantinib and cell viability was measured via the CCK-8 assay.…”

Section: Resultsmentioning

confidence: 99%

Human umbilical cord MSC‑derived hepatocyte growth factor enhances autophagy in AOPP‑treated HK‑2 cells

Zhang

Xie

et al. 2020

Exp Ther Med

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Mesenchymal stem cell (MSC) transplantation may serve as an important treatment modality in chronic kidney disease (CKD); however, the underlying mechanisms remain unclear. Advanced oxidation protein products (AOPP) have been demonstrated to induce renal tubular epithelial cell (RTEC) injury via autophagy inhibition. Therefore, the present study was performed to investigate the role of human umbilical cord-derived MSCs (hUC-MSCs) in RTEC autophagy. AOPP-treated HK-2 cells were co-cultured with hUC-MSCs or treated with recombinant humanized hepatocyte growth factor (HGF). Western blotting was used to detect the levels of autophagy-and PI3K/AKT/mTOR signaling pathway-related proteins, and immunofluorescence staining was used to detect the levels of autophagy-related proteins. The HGF protein levels in HK-2 cells and the hUC-MSC co-culture system were measured. The cells were subsequently treated with tivantinib, an HGF competitive inhibitor, and the levels of autophagy-related proteins were detected. Microtubule-associated protein 1 light chain 3B (LC3B) II/LC3B I (LC3II/LC3I) and beclin 1 protein levels were increased, while p62, PI3K, phosphorylated (p)-AKT and the p-mTOR protein levels were decreased in AOPP-treated HK-2 cells co-cultured with hUC-MSC, compared with the group treated with AOPP only. Furthermore, HGF expression was increased in AOPP-treated HK-2 cells co-cultured with hUC-MSC, compared with the group treated with AOPP alone. When HGF activity was inhibited using tivantinib, these effects on LC3II/LC3I, beclin 1, p62, PI3K, p-AKT, and p-mTOR expression were partially reversed. Furthermore, the effects of tivantinib were reversed by Ly294002. In conclusion, the present study revealed that hUC-MSCs partially reversed AOPP-mediated inhibition of autophagy in HK-2 cells via secretion of HGF, indicating that hUC-MSCs may serve as a potential therapy for preventing the progression of CKD.

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Section: Resultsmentioning

confidence: 99%

Human umbilical cord MSC‑derived hepatocyte growth factor enhances autophagy in AOPP‑treated HK‑2 cells

Zhang

Xie

et al. 2020

Exp Ther Med

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“…ERK can be activated by extracellular HGF/SF via its cognate receptor, c‐Met (c‐mesenchymal‐epithelial transition factor). In fact, the HGF/Met signalling pathway is importantly involved in pathogenesis of pancreatic cancer, and HGF/Met inhibitors are believed to become in near future crucial therapeutics for pancreatic cancer management . Importantly, HGF/SF then activates the signalling components, including Ras, that are required for the signal transduction from the c‐Met receptor towards the ERK pathway (Figure A).…”

Section: Resultsmentioning

confidence: 99%

“…In fact, the HGF/Met signalling pathway is importantly involved in pathogenesis of pancreatic cancer, and HGF/Met inhibitors are believed to become in near future crucial therapeutics for pancreatic cancer management. 28 Importantly, HGF/SF then activates the signalling components, including Ras, that are required for the signal transduction from the c-Met receptor towards the ERK pathway ( Figure 6A). ERK can also be activated more directly by 4HT, which converts ΔRaf-1:ER protein to an active form, and then subsequently activates the ERK pathway in a Ras-independent manner ( Figure 6A).…”

Section: Arthrospira Platensis Inhibits Erk Activity Upstream Of Ramentioning

confidence: 99%

Anti‐angiogenic effects of the blue‐green alga Arthrospira platensis on pancreatic cancer

Markova

Koníčková

Vaňková

et al. 2020

J Cellular Molecular Medi

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Arthrospira platensis, a blue‐green alga, is a popular nutraceutical substance having potent antioxidant properties with potential anti‐carcinogenic activities. The aim of our study was to assess the possible anti‐angiogenic effects of A platensis in an experimental model of pancreatic cancer. The effects of an A platensis extract were investigated on human pancreatic cancer cells (PA‐TU‐8902) and immortalized endothelial‐like cells (Ea.hy926). PA‐TU‐8902 pancreatic tumours xenografted to athymic mice were also examined. In vitro migration and invasiveness assays were performed on the tested cells. Multiple angiogenic factors and signalling pathways were analysed in the epithelial, endothelial and cancer cells, and tumour tissue. The A platensis extract exerted inhibitory effects on both migration and invasion of pancreatic cancer as well as endothelial‐like cells. Tumours of mice treated with A platensis exhibited much lesser degrees of vascularization as measured by CD31 immunostaining (P = .004). Surprisingly, the VEGF‐A mRNA and protein expressions were up‐regulated in pancreatic cancer cells. A platensis inhibited ERK activation upstream of Raf and suppressed the expression of ERK‐regulated proteins. Treatment of pancreatic cancer with A platensis was associated with suppressive effects on migration and invasiveness with various anti‐angiogenic features, which might account for the anticancer effects of this blue‐green alga.

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“…[12][13][14][15][16] Hepatocyte growth factor (HGF) is a cytokine produced by stromal cells (such as fibroblasts and macrophages) that acts on the c-met receptor on the surface of tumor cells. 17,18 HGF/ c-Met signaling plays an important role in promoting tumor growth, invasion, metastasis, and tumor angiogenesis. 19,20 Therefore, HGF/c-Met is a potential target site for antitumor therapy.…”

Section: Introductionmentioning

confidence: 99%

“…24,25 Research into anticancer treatments that target the NK4 pathway has become a popular topic. 17,26 Therefore, using NK4 as a liver-targeting ligand would not only actively recognize and bind to hepatocytes but also blocks the HGF/c-Met signaling pathway to play a synergistic anticancer role ( Figure 1). In recent years, reports have described decoration of liposomes with the HGF singlechain variable fragment (scFv), 27 and drug delivery systems mediated by scFv have shown great success as a potential in tumor-targeting therapy.…”

Section: Introductionmentioning

confidence: 99%

<p>Preparation, Characterization, and in vivo Evaluation of NK4-Conjugated Hydroxycamptothecin-Loaded Liposomes</p>

Zhou¹,

Zhang²,

Cheng³

et al. 2020

IJN

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In this study, NK4-conjugated hydroxycamptothecin liposomes (NK4-HCPT-Lips) were prepared with the aim of improving drug targeting to the liver. Methods: NK4-HCPT-Lips were prepared using the thin-film dispersion method. In vitro antitumor activities were evaluated by MTT assay. HCPT levels in plasma and tissues were determined via high-performance liquid chromatography (HPLC) with camptothecin as the internal standard, and the characteristics, pharmacokinetics, and bio-distribution of NK4-HCPT-Lips were evaluated. Results: The liposomes showed a regular spherical-shaped morphology, and the entrapment efficiency and drug loading capacity reached 82.5 ± 2.4% and 3.01 ± 0.23%, respectively, with a particle size of 155.6 ± 2.6 nm and a zeta potential of −24.8 ± 3.3 mV. Inhibition effect experiments found that NK4-HCPT-Lips had a good inhibition on the HepG2 cells. Pharmacokinetic studies revealed an increase in the area under the curve and mean residence time as well as a decrease in plasma clearance (p < 0.05) of the NK4-HCPT-Lips compared to those of HCPT liposomes and a commercial HCPT injection. Tissue distribution studies showed that NK4-HCPT-Lips were present at high levels in the liver but were cleared from the kidneys. Conclusion: These results demonstrate that NK4-HCPT-Lips possess excellent livertargeting attributes, which could enhance the therapeutic effects of drug treatments for hepatic diseases.

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Targeting the C-MET/HGF Signaling Pathway in Pancreatic Ductal Adenocarcinoma

Cited by 12 publications

References 81 publications

Human umbilical cord MSC‑derived hepatocyte growth factor enhances autophagy in AOPP‑treated HK‑2 cells

Human umbilical cord MSC‑derived hepatocyte growth factor enhances autophagy in AOPP‑treated HK‑2 cells

Anti‐angiogenic effects of the blue‐green alga Arthrospira platensis on pancreatic cancer

<p>Preparation, Characterization, and in vivo Evaluation of NK4-Conjugated Hydroxycamptothecin-Loaded Liposomes</p>

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