Exenatide induces autophagy and prevents the cell regrowth in HepG2 cells

Krause, Gabriele Catyana; Lima, Kelly Goulart; Levorse, Vitor Giancarlo Schneider; Haute, Gabriela Viegas; Gassen, Rodrigo Benedetti; Garcia, Maria Cláudia Rosa; Pedrazza, Leonardo; Donadio, Márcio Vinı́cius Fagundes; Luft, Carolina; Oliveira, Jarbas Rodrigues de

doi:10.17179/excli2019-1415

Cited by 9 publications

(8 citation statements)

References 29 publications

(33 reference statements)

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“…Exe-4 attenuated the protective effect of hyperglycemia. Studies have revealed that Exe-4 could inhibit cancer cell growth via different mechanisms ( 40 – 43 ). Krause et al ( 40 ) showed that exenatide induces cancer cell autophagy and prevents chemoresistance through mTOR modulation.…”

Section: Discussionmentioning

confidence: 99%

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The GLP-1R Agonist Exendin-4 Attenuates Hyperglycemia-Induced Chemoresistance in Human Endometrial Cancer Cells Through ROS-Mediated Mitochondrial Pathway

Zhang

Cheng

et al. 2021

Front. Oncol.

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This study aimed to assess the effects of the antidiabetic drug Exendin-4 (Exe-4), a GLP-1 receptor agonist, on the response of human endometrial cancer cells to chemotherapy under high glucose (HG) conditions. Cell viability was detected using a cell counting kit (CCK)-8. Cell apoptosis and reactive oxygen species (ROS) levels were measured by flow cytometry. Gene expression was evaluated by real-time PCR and immunoblotting. The chemotherapeutic drug cisplatin (DDP) dose-dependently inhibited both human endometrial adenocarcinoma Ishikawa and HEC1B cells, a response reversed by HG. Meanwhile, Exe-4 attenuated hyperglycemia’s effect by elevating intracellular lactate dehydrogenase (LDH) and ROS production. Similarly, DDP-induced elevation of intracellular rhodamine123 was attenuated by HG, and Exe-4 reversed HG’s impact. The chemoresistance genes multidrug resistance-associated protein 1 (MRP1) and P-glycoprotein (Pgp) were upregulated. At the same time, topoisomerase II (TOPO II) was downregulated under HG conditions, suggesting HG-induced chemoresistance. Exe-4 did not significantly influence the above genes. DDP downregulated Bcl-2 and Bcl-XL and upregulated Bax, cytosolic cytochrome c, and PARP under normal glucose (NG) versus HG conditions, and Exe-4 attenuated these effects. Upstream of Bax/Bcl, acetylated P53 was upregulated by DDP and downregulated by HG, whose effect was reversed by Exe-4. DPP treatment significantly induced apoptosis and cell cycle arrest in the S phase under NG, and HG reduced these effects. Prolonged exposure to HG induces DDP chemoresistance in human endometrial cancer cells but is alleviated by Exe-4.

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Section: Discussionmentioning

confidence: 99%

“…Studies have revealed that Exe-4 could inhibit cancer cell growth via different mechanisms ( 40 – 43 ). Krause et al ( 40 ) showed that exenatide induces cancer cell autophagy and prevents chemoresistance through mTOR modulation. Kanda et al ( 41 ) showed that liraglutide prevented Ishikawa cell growth by enhancing autophagy.…”

Section: Discussionmentioning

confidence: 99%

The GLP-1R Agonist Exendin-4 Attenuates Hyperglycemia-Induced Chemoresistance in Human Endometrial Cancer Cells Through ROS-Mediated Mitochondrial Pathway

Zhang

Cheng

et al. 2021

Front. Oncol.

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“…The formation of acidic vesicle organelles (AVOs) was analyzed using acridine orange (AO) dye (Sigma-Aldrich, USA). The dye emits green fluorescence in the nucleus and cytoplasm and red fluorescence when AVO formation occurs [13], indicating that the cells are in an autophagic process. HepG2 cells were seeded in 96-well plates (2.5 × 10 4 cells/ well) and treated with CPBMF65 (90 µM).…”

Section: Evaluation Of Autophagymentioning

confidence: 99%

“…Autophagy was also investigated in HepG2 cells using the AO dye, as this cellular mechanism involves degradation of unnecessary or non-functional components. CDDP (20 µM) was chosen as a positive control based on previous studies from our laboratory [13,18]. Cells were quantified using the flow cytometer and visualized under a fluorescent microscope (Fig.…”

Section: Cpbmf65 Treatment Promotes Senescence In Hepg2 Cellsmentioning

confidence: 99%

CPBMF65, a synthetic human uridine phosphorylase-1 inhibitor, reduces HepG2 cell proliferation through cell cycle arrest and senescence

et al. 2020

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Hepatocellular carcinoma (HCC) is the most prevalent type of tumor among primary liver tumors and is the second highest cause of cancer-related deaths worldwide. Current therapies are controversial, and more research is needed to identify effective treatments. A new synthetic compound, potassium 5-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-olate (CPBMF65), is a potent inhibitor of the human uridine phosphorylase-1 (hUP1) enzyme, which controls the cell concentration of uridine (Urd). Urd is a natural pyrimidine nucleoside involved in cellular processes, such as RNA synthesis. In addition, it is considered a promising biochemical modulator, as it may reduce the toxicity caused by chemotherapeutics without impairing its anti-tumor activity. Thus, the objective of this study is to evaluate the effects of CPBMF65 on the proliferation of the human hepatocellular carcinoma cell line (HepG2). Cell proliferation, cytotoxicity, apoptosis, senescence, autophagy, intracellular Urd levels, cell cycle arrest, and drug resistance were analyzed. Results demonstrate that, after incubation with CPBMF65, HepG2 cell proliferation decreased, mainly through cell cycle arrest and senescence, increasing the levels of intracellular Urd and maintaining cell proliferation reduced during chronic treatment. In conclusion, results show, for the first time, the ability of a hUP1 inhibitor (CPBMF65) to reduce HepG2 cell proliferation through cell cycle arrest and senescence.

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“…Exenatide (Exe), a glucagon-like peptide-1 analog, is regarded as an effective therapy of type 2 diabetes mellitus (T2DM; Gaede et al, 2019). Furthermore, exenatide is known to activate autophagy, thereby exerting beneficial effects for multiple pathologies, such as diabetic wounds, cardiac injury, hepatocellular carcinoma, and nonalcoholic fatty liver disease (Krause et al, 2019;Qi et al, 2017;Roan et al, 2017;Shao et al, 2018;Yu et al, 2018). Furthermore, Exe has been shown to reduce oxidative stress through attenuating ROS production via increasing the antioxidant enzymes manganesedependent superoxide dismutase (MnSOD) and catalase in diabetic cardiomyopathy (Ding et al, 2019).…”

mentioning

confidence: 99%

Exenatide improves random‐pattern skin flap survival via TFE3 mediated autophagy augment

Chen

Lou

et al. 2020

Journal Cellular Physiology

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Random‐pattern skin flaps are widely applied to rebuild and restore soft‐tissue damage in reconstructive surgery; however, ischemia and subsequent ischemia‐reperfusion injury lead to flap necrosis and are major complications. Exenatide, a glucagon‐like peptide‐1 analog, exerts therapeutic benefits for diabetic wounds, cardiac injury, and nonalcoholic fatty liver disease. Furthermore, Exenatide is a known activator of autophagy, which is a complex process of subcellular degradation that may enhance the viability of random skin flaps. In this study, we explored whether exenatide can improve skin flap survival. Our results showed that exenatide augments autophagy, increases flap viability, enhances angiogenesis, reduces oxidative stress, and alleviates pyroptosis. Coadministration of exenatide with 3‐methyladenine and chloroquine, potent inhibitors of autophagy, reversed the beneficial effects, suggesting that the therapeutic benefits of exenatide for skin flaps are due largely to autophagy activation. Mechanistically, we identified that exenatide enhanced activation and nuclear translocation of TFE3, which leads to autophagy activation. Furthermore, we found that exenatide activates the AMPK–SKP2–CARM1 and AMPK–mTOR signaling pathways, which likely lead to exenatide's effects on activating TFE3. Overall, our findings suggest that exenatide may be a potent therapy to prevent flap necrosis, and we also reveal novel mechanistic insight into exenatide's effect on flap survival.

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Exenatide induces autophagy and prevents the cell regrowth in HepG2 cells

Cited by 9 publications

References 29 publications

The GLP-1R Agonist Exendin-4 Attenuates Hyperglycemia-Induced Chemoresistance in Human Endometrial Cancer Cells Through ROS-Mediated Mitochondrial Pathway

The GLP-1R Agonist Exendin-4 Attenuates Hyperglycemia-Induced Chemoresistance in Human Endometrial Cancer Cells Through ROS-Mediated Mitochondrial Pathway

CPBMF65, a synthetic human uridine phosphorylase-1 inhibitor, reduces HepG2 cell proliferation through cell cycle arrest and senescence

Exenatide improves random‐pattern skin flap survival via TFE3 mediated autophagy augment

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