Exenatide modulates tumor–endothelial cell interactions in human ovarian cancer cells

Kosowska, Agnieszka; Gallego‐Colon, Enrique; Garczorz, Wojciech; Kłych-Ratuszny, Agnieszka; Aghdam, Mohammad Reza F.; ́niak, Michał Woz; Witek, Andrzej; Wróblewska-Czech, Agnieszka; Cygal, Anna; Francuz, Tomasz

doi:10.1530/ec-17-0294

Cited by 17 publications

(10 citation statements)

References 49 publications

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“…As previously reported, the GLP-1R agonist inhibited TNFα/LPS-induced THP-1 monocyte-endothelial adhesion via reduction of the protein expression of adhesion molecules VCAM-1 [32]. Similarly, GLP-1 analog also modulated tumor-endothelial cell interactions through reducing production of adhesion molecules (ICAM-1 and VCAM-1) [33]. Additionally, the GLP-1 analog suppressed the expression of cell adhesion molecules including ICAM-1 and VCAM-1 in diabetic We previously demonstrated that mice with LPS-induced ALI benefited from Rho inhibition [24].…”

Section: Discussionsupporting

confidence: 69%

Glucagon-like peptide-1 receptor activation alleviates lipopolysaccharide-induced acute lung injury in mice via maintenance of endothelial barrier function

Wei

Wang

et al. 2019

Laboratory Investigation

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Glucagon-like peptide-1 (GLP-1), which is well known for regulating glucose homeostasis, exhibits multiple actions in cardiovascular disorders and renal injury. However, little is known about the effect of GLP-1 receptor (GLP-1R) activation on acute lung injury (ALI). In this study, we investigated the effect of GLP-1R on ALI and the potential underlying mechanisms with the selective agonist liraglutide. Our results show that GLP-1 levels decreased in serum, though they increased in bronchoalveolar lavage fluid (BALF) and lung tissue in a mouse model of lipopolysaccharide (LPS)-induced ALI. Liraglutide prevented LPS-induced polymorphonuclear neutrophil (PMN) extravasation, lung injury, and alveolarcapillary barrier dysfunction. In cultured human pulmonary microvascular endothelial cells (HPMECs), liraglutide protected against LPS-induced endothelial barrier injury by restoring intercellular tight junctions and adherens junctions. Moreover, liraglutide prevented PMN-endothelial adhesion by inhibiting the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and thereafter suppressed PMN transendothelial migration. Furthermore, liraglutide suppressed LPS-induced activation of Rho/NF-κB signaling in HPMECs. In conclusion, our results show that GLP-1R activation protects mice from LPS-induced ALI by maintaining functional endothelial barrier and inhibiting PMN extravasation. These results also suggest that GLP-1R may be a potential therapeutic target for the treatment of ALI.

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Section: Discussionsupporting

confidence: 69%

Glucagon-like peptide-1 receptor activation alleviates lipopolysaccharide-induced acute lung injury in mice via maintenance of endothelial barrier function

Wei

Wang

et al. 2019

Laboratory Investigation

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“…Indeed, the GLP-1 receptor agonist Exendin-4 has been reported to decrease proliferation of prostate cancer cells by a PKA-dependent mechanism, and attenuate prostate cancer growth in a tumor xenograft mouse model (42). Exendin-4 was also shown to inhibit migration and promote apoptosis in ovarian cancer cells (43). Therefore, PKA-dependent inactivation of CaMKK2 may provide a potential mechanism for the anti-proliferative effects of Exendin-4 in both prostate and ovarian cancers.…”

Section: Discussionmentioning

confidence: 99%

CaMKK2 is inactivated by cAMP-PKA signaling and 14-3-3 adaptor proteins

Langendorf

O’Brien

Ngoei

et al. 2020

Journal of Biological Chemistry

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The calcium-calmodulin (Ca2+-CaM) dependent protein kinase kinase-2 (CaMKK2) is a key regulator of cellular and whole-body energy metabolism. It is known to be activated by increases in intracellular Ca2+, but the mechanisms by which it is inactivated are less clear. CaMKK2 inhibition protects against prostate cancer, hepatocellular carcinoma and metabolic derangements induced by a high-fat diet, therefore elucidating the intracellular mechanisms that inactivate CaMKK2 has important therapeutic implications. Here we show that stimulation of cyclic AMP (cAMP)-dependent protein kinase (PKA) signaling in cells inactivates CaMKK2 by phosphorylation of three conserved serine residues. PKA-dependent phosphorylation of Ser495 directly impairs Ca2+-CaM activation, whereas phosphorylation of Ser100 and Ser511 mediate recruitment of 14-3-3 adaptor proteins that hold CaMKK2 in the inactivated state by preventing dephosphorylation of phospho-Ser495. We also report the crystal structure of 14-3-3ζ bound to a synthetic diphosphorylated peptide that reveals how the canonical (Ser511) and non-canonical (Ser100) 14-3-3 consensus sites on CaMKK2 co-operate to bind 14-3-3 proteins. Our findings provide detailed molecular insights into how cAMP-PKA signaling inactivates CaMKK2 and reveals a pathway to inhibit CaMKK2 with potential for treating human diseases.

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“…In addition, the induction of apoptosis was confirmed by fluorescent techniques using the caspase-3/7 detection reagent. Treatment with the FHRH extract resulted in bright fluorescent nuclei (Figure 4), a hallmark of cells undergoing apoptosis [34].…”

Section: Discussionmentioning

confidence: 99%

Effects of Hexane Root Extract ofFerula hermonisBoiss. on Human Breast and Colon Cancer Cells: AnIn VitroandIn VivoStudy

Abutaha

Nasr

Al-Zharani

et al. 2019

BioMed Research International

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Breast and colon cancers are leading causes of cancer-related deaths globally. Plants are a potential source of natural products that may be used for the treatment of cancer. Ferula hermonis (FH) is reported to have diverse therapeutic effects. However, there are few reports on the in vitro anticancer potential of FH extract. Our results showed that the Ferula hermonis root hexane extract (FHRH) can induce dose-dependent cytotoxic effects in breast and colon cancer cells with MTT IC50 values of 18.2 and 25 μg/ml, respectively. The FHRH extract induced apoptosis in both breast and colon cancer cells; this was confirmed by light and nuclear staining, q-PCR, and caspase 3/7 activation. This study also demonstrated the antitumor activity of FHRH in 9,10-dimethylbenz[α]anthracene DMBA-induced rodent mammary tumor model. The GC/MS analysis revealed the presence of 3,5-Dimethylbenzenemethanol, Alpha-Bisabolol, Alpha-pinene, Beta-pinene, and Baccatin III that have various pharmacological potentials. Overall, the present study suggests that FHRH extract possesses anticancer potential which is mediated through apoptotic effects in MDA-MB-231 and LoVo cells. The present study also considered a basis for further investigations into the potential use of FHRH extract as an anticancer therapy for breast and colon cancers.

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Exenatide modulates tumor–endothelial cell interactions in human ovarian cancer cells

Cited by 17 publications

References 49 publications

Glucagon-like peptide-1 receptor activation alleviates lipopolysaccharide-induced acute lung injury in mice via maintenance of endothelial barrier function

Glucagon-like peptide-1 receptor activation alleviates lipopolysaccharide-induced acute lung injury in mice via maintenance of endothelial barrier function

CaMKK2 is inactivated by cAMP-PKA signaling and 14-3-3 adaptor proteins

Effects of Hexane Root Extract ofFerula hermonisBoiss. on Human Breast and Colon Cancer Cells: AnIn VitroandIn VivoStudy

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