Vitronectin, fibronectin and epidermal growth factor induce proliferation via the JNK and ERK pathways in insulinoma INS-1 cells

Kaçar, Ayşe Karatuğ; Bolkent, Şehnaz

doi:10.1007/s10616-018-0277-6

Cited by 4 publications

(3 citation statements)

References 45 publications

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“…Studies showed that both the insulin and NGF immunofluorescent labelling was weaker in insulinoma samples (Vidaltamayo et al 2003). Epidermal growth factor (EGF) appears in pancreatic ductal adenocarcinomas, and an in vitro study showed increase in level of JNK after administration of EGF, vitronectin and fibronectin in insulinoma cells (Kacar and Bolkent 2019).…”

Section: Discussionmentioning

confidence: 99%

PACAP and PAC1 Receptor Expression in Human Insulinomas

Ferencz

Tóth

Kaszás

et al. 2021

Int J Pept Res Ther

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Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with widespread occurrence and diverse functions. PACAP binds to specific PAC1 and non-specific VPAC1/2 receptors. PACAP is considered as a growth factor, as it plays important roles during development and participates in reparative processes. Highest concentrations are found in the nervous system and endocrine glands, where several functions are known, including actions in tissue growth, differentiation and tumour development. Therefore, we have investigated expression of PACAP and its receptors in different tumours, including those of endocrine glands. We showed earlier that PACAP and PAC1 receptor staining intensity decreased in pancreatic ductal adenocarcinoma. In the present study we aimed to investigate alterations of PACAP and PAC1 receptor in human insulinoma and compared the immunostaining pattern with samples from chronic pancreatitis patients. We collected perioperative and histological data of patients who underwent operation because of insulinoma or chronic pancreatitis over a five-year-long period. Histology showed chronic pancreatitis with severe scar formation in pancreatitis patients, while tumour samples evidenced Grade 1 or 2 insulinoma. PACAP and PAC1 receptor expression was studied using immunohistochemistry. Staining intensity was very strong in the Langerhans islets of normal tissue and discernible staining was also observed in the exocrine pancreas. Immunostaining intensity for both PACAP and PAC1 receptor was markedly weaker in insulinoma samples, and disappeared from chronic pancreatitis samples except for intact islets. These findings show that PAC1 receptor/PACAP signalling is altered in insulinoma and this suggests a possible involvement of this system in tumour growth or differentiation.

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Section: Discussionmentioning

confidence: 99%

PACAP and PAC1 Receptor Expression in Human Insulinomas

Ferencz

Tóth

Kaszás

et al. 2021

Int J Pept Res Ther

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“…Parallel to other MAPKs, the JNK pathway is important for proliferation. Phosphorylation of JNK contributes to proliferation of lung adenocarcinoma cells, potentiates hepatocellular carcinoma and colorectal cancer progression and metastases (Xiao et al., 2016; Chan et al., 2017; Karatug Kacar et al., 2019; Cao et al., 2020). Furthermore, activation of JNK was related with increased proliferation and growth of human pancreatic cancer (Choi et al., 2018).…”

Section: Discussionmentioning

confidence: 99%

Pancreatic stellate cells exhibit adaptation to oxidative stress evoked by hypoxia

Estarás

Martínez-Morcillo

García

et al. 2020

Biology of the Cell

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Background information. Pancreatic stellate cells play a key role in the fibrosis that develops in diseases such as pancreatic cancer. In the growing tumour, a hypoxia condition develops under which cancer cells are able to proliferate. The growth of fibrotic tissue contributes to hypoxia. In this study, the effect of hypoxia (1% O 2) on pancreatic stellate cells physiology was investigated. Changes in intracellular free-Ca 2+ concentration, mitochondrial free-Ca 2+ concentration and mitochondrial membrane potential were studied by fluorescence techniques. The status of enzymes responsible for the cellular oxidative state was analyzed by quantitative reverse transcriptionpolymerase chain reaction, high-performance liquid chromatography, spectrophotometric and fluorimetric methods and by Western blotting analysis. Cell viability and proliferation were studied by crystal violet test, 5-bromo-2deoxyuridine cell proliferation test and Western blotting analysis. Finally, cell migration was studied employing the wound healing assay. Results. Hypoxia induced an increase in intracellular and mitochondrial free-Ca 2+ concentration, whereas mitochondrial membrane potential was decreased. An increase in mitochondrial reactive oxygen species production was observed. Additionally, an increase in the oxidation of proteins and lipids was detected. Moreover, cellular total antioxidant capacity was decreased. Increases in the expression of superoxide dismutase 1 and 2 were observed and superoxide dismutase activity was augmented. Hypoxia evoked a decrease in the oxidized/reduced glutathione ratio. An increase in the phosphorylation of nuclear factor erythroid 2-related factor and in expression of the antioxidant enzymes catalytic subunit of glutamate-cysteine ligase, catalase, NAD(P)H-quinone oxidoreductase 1 and heme oxygenase-1 were detected. The expression of cyclin A was decreased, whereas expression of cyclin D and the content of 5-bromo-2-deoxyuridine were increased. This was accompanied by an increase in cell viability. The phosphorylation state of c-Jun NH 2-terminal kinase was increased, whereas that of p44/42 and p38 was decreased. Finally, cells subjected to hypoxia maintained migration ability. Conclusions and Significance. Hypoxia creates pro-oxidant conditions in pancreatic stellate cells to which cells adapt and leads to increased viability and proliferation.

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“…It has been suggested that the JNK pathway plays a pivotal role in cell proliferation. JNK is phosphorylated in lung adenocarcinoma cells, hepatocellular carcinoma, colorectal cancer and pancreatic cancer, where it contributes to the progression of malignant cells and metastases [ 57 , 58 , 59 , 60 , 61 ]. Moreover, JNK phosphorylation is increased in PSCs subjected to hypoxia, and its inhibition is related to a decrease in cell viability [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

Melatonin Induces Apoptosis and Modulates Cyclin Expression and MAPK Phosphorylation in Pancreatic Stellate Cells Subjected to Hypoxia

Estarás

Gonzalez

Fernandez–Bermejo

et al. 2021

IJMS

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In certain diseases of the pancreas, pancreatic stellate cells form an important part of fibrosis and are critical for the development of cancer cells. A hypoxic condition develops within the tumor, to which pancreatic stellate cells adapt and are able to proliferate. The consequence is the growth of the tumor. Melatonin, the product of the pineal gland, is gaining attention as an agent with therapeutic potential against pancreatic cancers. Its actions on tumor cells lead, in general, to a reduction in cell viability and proliferation. However, its effects on pancreatic stellate cells subjected to hypoxia are less known. In this study, we evaluated the actions of pharmacological concentrations of melatonin (1 mM–1 µM) on pancreatic stellate cells subjected to hypoxia. The results show that melatonin induced a decrease in cell viability at the highest concentrations tested. Similarly, the incorporation of BrdU into DNA was diminished by melatonin. The expression of cyclins A and D also was decreased in the presence of melatonin. Upon treatment of cells with melatonin, increases in the expression of major markers of ER stress, namely BIP, phospho-eIF2α and ATF-4, were detected. Modulation of apoptosis was noticed as an increase in caspase-3 activation. In addition, changes in the phosphorylated state of p44/42, p38 and JNK MAPKs were detected in cells treated with melatonin. A slight decrease in the content of α-smooth muscle actin was detected in cells treated with melatonin. Finally, treatment of cells with melatonin decreased the expression of matrix metalloproteinases 2, 3, 9 and 13. Our observations suggest that melatonin, at pharmacological concentrations, diminishes the proliferation of pancreatic stellate cells subjected to hypoxia through modulation of cell cycle, apoptosis and the activation of crucial MAPKs. Cellular responses might involve certain ER stress regulator proteins. In view of the results, melatonin could be taken into consideration as a potential therapeutic agent for pancreatic fibrosis.

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Vitronectin, fibronectin and epidermal growth factor induce proliferation via the JNK and ERK pathways in insulinoma INS-1 cells

Cited by 4 publications

References 45 publications

PACAP and PAC1 Receptor Expression in Human Insulinomas

PACAP and PAC1 Receptor Expression in Human Insulinomas

Pancreatic stellate cells exhibit adaptation to oxidative stress evoked by hypoxia

Melatonin Induces Apoptosis and Modulates Cyclin Expression and MAPK Phosphorylation in Pancreatic Stellate Cells Subjected to Hypoxia

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