UCP2 inhibition induces ROS/Akt/mTOR axis: Role of GAPDH nuclear translocation in genipin/everolimus anticancer synergism

Dando, Ilaria; Pacchiana, Raffaella; Pozza, Elisa Dalla; Cataldo, Ivana; Bruno, Stefano; Conti, Paola; Cordani, Marco; Grimaldi, Anna; Butera, Giovanna; Caraglia, Michele; Scarpa, Aldo; Palmieri, Marta; Donadelli, Massimo

doi:10.1016/j.freeradbiomed.2017.09.022

Cited by 56 publications

(57 citation statements)

References 43 publications

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“…Studies have demonstrated that mitochondrial uncoupling protein 2 (UCP2) leads to tumor resistance to multiple anticancer drugs by reducing ROS generated by mitochondrial metabolism. Dando et al [36] proved that the combination of genipin and everolimus could synergistically inhibit the growth of pancreatic adenocarcinoma (PAAD) cells and induce autophagy of tumor cells. This is because inhibition of UCP2 in PADD cells activates the Akt/mTOR pathway by a ROS dependent mechanism, which reduces the anti-proliferation effect of UCP2 inhibitor genipin.…”

Section: The Tumors Of Digestive Systemmentioning

confidence: 99%

mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges

et al. 2020

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Mammalian target of rapamycin (mTOR) regulates cell proliferation, autophagy, and apoptosis by participating in multiple signaling pathways in the body. Studies have shown that the mTOR signaling pathway is also associated with cancer, arthritis, insulin resistance, osteoporosis, and other diseases. The mTOR signaling pathway, which is often activated in tumors, not only regulates gene transcription and protein synthesis to regulate cell proliferation and immune cell differentiation but also plays an important role in tumor metabolism. Therefore, the mTOR signaling pathway is a hot target in anti-tumor therapy research. In recent years, a variety of newly discovered mTOR inhibitors have entered clinical studies, and a variety of drugs have been proven to have high activity in combination with mTOR inhibitors. The purpose of this review is to introduce the role of mTOR signaling pathway on apoptosis, autophagy, growth, and metabolism of tumor cells, and to introduce the research progress of mTOR inhibitors in the tumor field.

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Section: The Tumors Of Digestive Systemmentioning

confidence: 99%

mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges

et al. 2020

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“…UCP2 involvement has been reported in many diseases. For example, increased expression of UCP2 can suppress glucose-stimulated insulin secretion, and inhibition of UCP2 expression was shown to decrease the growth of PaCa44 human pancreatic cancer cells [32,33]. UCP2 can regulate the proliferation and differentiation of neural stem cells by inhibiting ROS production, and UCP2 overexpression can decrease basal autophagy [34][35][36].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Uncoupling Protein 2 Enhances the Radiosensitivity of Cervical Cancer Cells by Promoting the Production of Reactive Oxygen Species

Liu

Huang

Dong

et al. 2020

Oxidative Medicine and Cellular Longevity

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Objective. The mechanism of enhanced radiosensitivity induced by mitochondrial uncoupling protein UCP2 was investigated in HeLa cells to provide a theoretical basis as a novel target for cervical cancer treatment. Methods. HeLa cells were irradiated with 4 Gy X-radiation at 1.0 Gy/min. The expression of UCP2 mRNA and protein was assayed by real-time quantitative polymerase chain reaction and western blotting. UCP2 siRNA and negative control siRNA fragments were constructed and transfected into HeLa cells 24 h after irradiation. The effect of UCP2 silencing and irradiation on HeLa cells was determined by colony formation, CCK-8 cell viability, γH2AX immunofluorescence assay of DNA damage, Annexin V-FITC/PI apoptosis assay, and propidium iodide cell cycle assay. The effects on mitochondrial structure and function were investigated with fluorescent probes including dichlorodihydrofluorescein diacetate (DCFH-DA) assay of reactive oxygen species (ROS), rhodamine 123, and MitoTracker Green assay of mitochondrial structure and function. Results. Irradiation upregulated UCP2 expression, and UCP2 knockdown decreased the survival of irradiated HeLa cells. UCP2 silencing sensitized HeLa cells to irradiation-induced DNA damage and led to increased apoptosis, cell cycle arrest in G2/M, and increased mitochondrial ROS. Increased radiosensitivity was associated with an activation of P53, decreased Bcl-2, Bcl-xl, cyclin B, CDC2, Ku70, and Rad51 expression, and increased Apaf-1, cytochrome c, caspase-3, and caspase-9 expression. Conclusions. UCP2 inhibition augmented the radiosensitivity of cervical cancer cells, and it may be a potential target of radiotherapy of advanced cervical cancer.

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“…The assessment of direct cytotoxicity on cancer cells, often in combination with the measurement of apoptosis events, are common in vitro assays employed to show potential anticancer effects of natural products. Genipin and geniposide have been shown to be cytotoxic in numerous cancer cell types including colorectal cancer [ 35 , 36 ], pancreatic adenocarcinoma cells [ 37 ], AGS and SNU638 human gastric carcinoma cells [ 38 , 39 , 40 ], non-small-cell lung cancer H1299 cells [ 41 ], prostate (DU145 and PC3) cancer cells [ 42 , 43 , 44 ], hepatocarcinoma (HepG2 and Hep3B) cells [ 45 , 46 ] breast cancer (MDA-MB-231) cells [ 47 ], human leukaemia (K562, HL-60, U266, U937) cells [ 48 , 49 , 50 ], and tongue squamous carcinoma (HSC-3) cells. The acetylated product of geniposide, penta-acetyl geniposide ( Figure 1 ), has also been investigated and has shown in vitro cytotoxicity in a range of cell lines, such as C6 glioma cells [ 51 , 52 , 53 , 54 , 55 , 56 , 57 ].…”

Section: Anticancer Effects Of Geniposide and Genipinmentioning

confidence: 99%

“…Even for its acetate derivative, which is considered more active, many studies used 200 or 300 μM as effective doses (e.g., [ 55 , 60 ], while some studies even used 600 μM (e.g., [ 53 ]). On the other hand, for the anticancer compound genipin (more active in vitro than geniposide), which displays cancer growth inhibition at a lower micromolar range concentrations, the most effective doses shown in various studies remain around 100 and 200 μM [ 35 , 37 , 42 , 45 , 48 , 61 ]. In this regard, the IC 50 of genipin in H1299 cells was 351.5 μM [ 41 ].…”

Section: Anticancer Effects Of Geniposide and Genipinmentioning

confidence: 99%

“…Through the effect related to UCP2 inhibition, Mailloux et al [ 176 ] have shown that drug-resistant leukemic cells could be sensitized to the cytotoxic action of menadione, doxorubicin, and epirubicin when co-treated with genipin. Dando et al [ 37 ] also studied the crosstalk between UCP2 inhibition and the ROS/Akt/mechanistic target of rapamycin (mTOR) axis for genipin/everolimus anticancer synergism. In their study, employing mice xenografts of pancreatic adenocarcinoma and in vitro experiments, inhibition of UCP2 by genipin triggered the Akt/mTOR pathway by a ROS-dependent mechanism.…”

Section: Drug Potentiationmentioning

confidence: 99%

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Plant-Derived Anticancer Agents: Lessons from the Pharmacology of Geniposide and Its Aglycone, Genipin

Habtemariam

Lentini

2018

Biomedicines

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For centuries, plants have been exploited by mankind as sources of numerous cancer chemotherapeutic agents. Good examples of anticancer compounds of clinical significance today include the taxanes (e.g., taxol), vincristine, vinblastine, and the podophyllotoxin analogues that all trace their origin to higher plants. While all these drugs, along with the various other available therapeutic options, brought some relief in cancer management, a real breakthrough or cure has not yet been achieved. This critical review is a reflection on the lessons learnt from decades of research on the iridoid glycoside geniposide and its aglycone, genipin, which are currently used as gold standard reference compounds in cancer studies. Their effects on tumour development (carcinogenesis), cancer cell survival, and death, with particular emphasis on their mechanisms of actions, are discussed. Particular attention is also given to mechanisms related to the dual pro-oxidant and antioxidant effects of these compounds, the mitochondrial mechanism of cancer cell killing through reactive oxygen species (ROS), including that generated through the uncoupling protein-2 (UCP-2), the inflammatory mechanism, and cell cycle regulation. The implications of various studies for the evaluation of glycosidic and aglycone forms of natural products in vitro and in vivo through pharmacokinetic scrutiny are also addressed.

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UCP2 inhibition induces ROS/Akt/mTOR axis: Role of GAPDH nuclear translocation in genipin/everolimus anticancer synergism

Cited by 56 publications

References 43 publications

mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges

mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges

Inhibition of Uncoupling Protein 2 Enhances the Radiosensitivity of Cervical Cancer Cells by Promoting the Production of Reactive Oxygen Species

Plant-Derived Anticancer Agents: Lessons from the Pharmacology of Geniposide and Its Aglycone, Genipin

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