Metformin-induced anticancer activities: recent insights

AbstractMetformin is a widely used antidiabetic drug, and there is evidence among diabetic patients that metformin is a chemopreventive agent against multiple cancers. There is also evidence in human studies that metformin is a cancer chemotherapeutic agent, and several clinical trials that use metformin alone or in combination with other drugs are ongoing.In vivoandin vitrocancer cell culture studies demonstrate that metformin induces both AMPK-dependent and AMPK-independent genes/pathways that result in inhibition of cancer cell growth and migration and induction of apoptosis. The effects of metformin in cancer cells resemble the patterns observed after treatment with drugs that downregulate specificity protein 1 (Sp1), Sp3 and Sp4 or by knockdown of Sp1, Sp3 and Sp4 by RNA interference. Studies in pancreatic cancer cells clearly demonstrate that metformin decreases expression of Sp1, Sp3, Sp4 and pro-oncogenic Sp-regulated genes, demonstrating that one of the underlying mechanisms of action of metformin as an anticancer agent involves targeting of Sp transcription factors. These observations are consistent with metformin-mediated effects on genes/pathways in many other tumor types.

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Mitochondrial supercomplex assembly promotes breast and endometrial tumorigenesis by metabolic alterations and enhanced hypoxia tolerance

Nature Communications ◽

10.1038/s41467-019-12124-6 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 15

Author(s):

Kazuhiro Ikeda ◽

Kuniko Horie-Inoue ◽

Takashi Suzuki ◽

Rutsuko Hobo ◽

Norie Nakasato ◽

...

Keyword(s):

Endometrial Cancer ◽

Cell Growth ◽

Cancer Cells ◽

Cancer Cell ◽

Tricarboxylic Acid Cycle ◽

Hypoxia Tolerance ◽

Breast Cancer Patients ◽

Cancer Cell Growth

Abstract Recent advance in cancer research sheds light on the contribution of mitochondrial respiration in tumorigenesis, as they efficiently produce ATP and oncogenic metabolites that will facilitate cancer cell growth. Here we show that a stabilizing factor for mitochondrial supercomplex assembly, COX7RP/COX7A2L/SCAF1, is abundantly expressed in clinical breast and endometrial cancers. Moreover, COX7RP overexpression associates with prognosis of breast cancer patients. We demonstrate that COX7RP overexpression in breast and endometrial cancer cells promotes in vitro and in vivo growth, stabilizes mitochondrial supercomplex assembly even in hypoxic states, and increases hypoxia tolerance. Metabolomic analyses reveal that COX7RP overexpression modulates the metabolic profile of cancer cells, particularly the steady-state levels of tricarboxylic acid cycle intermediates. Notably, silencing of each subunit of the 2-oxoglutarate dehydrogenase complex decreases the COX7RP-stimulated cancer cell growth. Our results indicate that COX7RP is a growth-regulatory factor for breast and endometrial cancer cells by regulating metabolic pathways and energy production.

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COL11A1 is the Key Target Gene of MIST1 on Tumor Progression of Pancreatic Cancer

10.21203/rs.3.rs-793040/v1 ◽

2021 ◽

Author(s):

Yang Li ◽

Zhiqiang Liu ◽

Ying Sun ◽

Dianyun Ren ◽

Yongfeng Li ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Progression ◽

Cancer Cells ◽

Target Gene ◽

Animal Experiments ◽

Migration And Invasion ◽

Cancer Cell Growth ◽

Pancreatic Cancer Cells

Abstract Background: MIST1, a component of BHLH transcription factors, has been documented to be an important factor in tumor progression of pancreatic cancer, but the molecular mechanism is still unknown.Methods: COL11A1 was screened as a candidate key target gene of MIST1 in pancreatic cancer by ChIP -seq assay and verified by RT-PCR and Western Blotting on MIST1-overexpression pancreatic cancer cells. ChIP and dual-luciferase assays were performed to study the binding domain of MIST1 and COL11A1. Transwell invasion, wound healing, MTT, colony formation assays and animal experiments were performed to investigate the roles of COL11A1 expression on pancreatic cancer cells. Clinical data and TCGA datasets were used to evaluate the role of COL11A1 expression on prognosis for patients with pancreatic cancer.Results: MIST1 could bind to the promoter of COL11A1 as a negative transcription factor in pancreatic cancer. Overexpression of COL11A1 promotes pancreatic cancer cell growth, migration and invasion in vitro and in vivo. Expression of COL11A1 was upregulated in pancreatic cancer and positively correlated with a worse prognosis for patients with pancreatic cancer. Conclusions: These results demonstrated COL11A1 as a carcinogen in pancreatic cancer, and it acts as the key target gene of MIST1 on tumor progression of pancreatic cancer. COL11A1 can act as a potential therapeutic target of pancreatic cancer which is superior to MIST1.

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Investigation of metformin as a radiation sensitizer in pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.253 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 253-253

Author(s):

Jennifer Anne Dorth ◽

Gina Ferris ◽

Johnathan Zeng ◽

Scott Welford

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Clonogenic Survival ◽

Human Pancreatic Cancer ◽

Diabetic Patients ◽

Direct Effects ◽

M Cell ◽

Pancreatic Cancer Cells

253 Background: Clinical study demonstrates that diabetic patients taking metformin while undergoing chemotherapy and/or radiation for localized pancreatic cancer have improved overall survival compared to diabetics not taking metformin or non-diabetic patients (Sadeghi, Clin Cancer Res 2012). Metformin may act as a radiosensitizer through direct effects on cancer cells and/or indirect effects on the host, such as the inhibition of hepatic gluconeogenesis or inflammation (Pollak, Clin Cancer Res 2012). In vitro study demonstrates that the direct effects of metformin include suppression of mTOR, G2/M cell cycle arrest, and toxicity to cancer stem cells with resultant increase in chemo and radiosensitivity, though some of these studies employed supra-physiologic doses of metformin (1-10mM) instead of physiologic doses (10uM) (Song, Sci Rep 2012; Sanli, IJROBP 2010). Methods: MiaPaCa-2 human pancreatic cancer cells were grown in physiologic (5mM) or supra-physiologic (25mM) glucose media. After exposure to metformin (10uM or 10mM) for 3-7 days in cell culture, phosphorylation of AMPK, a target of metformin, was measured by western blot and radiation survival was determined by clonogenic survival assay. Results: MiaPaCa-2 cells grown in 5mM glucose media with metformin have higher levels of AMPK phosphorylation than those grown in 25mM glucose media or without metformin. Radiation clonogenic survival was similar between cells exposed to any of the treatment conditions, including differences in glucose concentration and/or presence of metformin. Conclusions: MiaPaCa-2 pancreatic cancer cells do not demonstrate enhanced radiosensitivity to metformin in vitro. Future studies will investigate whether K-Ras wild-type cell lines exhibit enhanced radiosensitivity to metformin in vitro and whether metformin acts as a radiosensitizer in vivo.

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TGF-βRII knock-down promotes tumor growth and chemoresistance to gemcitabine of pancreatic cancer cells via phosphorylation of STAT3

10.1101/352963 ◽

2018 ◽

Author(s):

Vincent Drubay ◽

Nicolas Skrypek ◽

Lucie Cordiez ◽

Romain Vasseur ◽

Céline Schulz ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Cancer Cell ◽

Pancreatic Cancer Cell ◽

Locally Advanced ◽

Pancreatic Cancer Cells ◽

The Impact

AbstractPancreatic adenocarcinoma (PDAC) is one of the most deadly cancers in the western countries because of a lack of early diagnostic markers and efficient therapeutics. At the time of diagnosis, more than 80% of patients have metastasis or locally advanced cancer and are therefore not eligible for surgical resection. Pancreatic cancer cell also harbour a high resistance to chemotherapeutic drugs such as gemcitabine that is one of the main palliative treatment for PDAC.TGF-β possesses both tumor-suppressive and oncogenic activities in pancreatic cancer. TGF-β signalling pathway plays complex role during carcinogenesis by initially inhibiting epithelial growth and later promoting the progression of advanced tumors and thus emerged as tumor suppressor pathway. TGF-β binds to its receptor TGF-βRII and activates different pathways: canonical pathway involving the Smad proteins and alternative pathways such as MAPKs. Smad4 is mutated in 50-80% of PDAC. Mutations of TGF-βRII also occurs (5-10%). In order to decipher the role of TGF-β in carcinogenesis and chemoresistance, we decided to characterize the knocking down of TGF-βRII that is the first actor of TGF-β signalling. We developed pancreatic cancer cell lines stably invalidated for TGF-βRII and studied the impact on biological properties of pancreatic cancer cells both in vitro and in vivo. We show that TGF-βRII silencing alters tumor growth and migration as well as resistance to. TGF-βRII silencing also leads to S727 STAT3 and S-63 c-Jun phosphorylation, decrease of MRP3 and increase of MRP4 ABC transporter expression and induction of a partial EMT phenotype.In the future, the better understanding TGF-β signaling pathways and underlying cellular mechanisms in chemoresistance to gemcitabine may bring new therapeutic tools to clinicians.

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LncRNA CTD-3252C9.4 modulates pancreatic cancer cell survival and apoptosis through regulating IFI6 transcription

Cancer Cell International ◽

10.1186/s12935-021-02142-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Xin Yin ◽

Jingyan Yang ◽

Jintian Chen ◽

Ruiqi Ni ◽

Yanhao Zhou ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Pancreatic Cancer Cell ◽

Luciferase Reporter ◽

Downstream Target ◽

Pancreatic Cancer Cells ◽

Cancer Cell Survival

Abstract Background Pancreatic cancer (PC) is one of the most lethal cancer types with high degree of malignancy and poor prognosis. Recent studies have shown that long non-coding RNAs (lncRNAs) were associated with the initiation and progression of pancreatic cancer. In the current study, we have investigated the expression, biological function and mechanism of a lncRNA CTD-3252C9.4 in pancreatic cancer. Methods The expression of CTD-3252C9.4 in pancreatic cancer cells and tissues was measured by qRT-PCR. In vitro and in vivo functional experiments assays were implemented for identifying CTD-3252C9.4 function in pancreatic cancer. Molecular relationships among CTD-3252C9.4, IRF1 and IFI6 were investigated via luciferase reporter assay, pulldown assay and ChIP assays. Results CTD-3252C9.4 was found remarkably decreased in pancreatic cancer cells and tissues. Overexpression of CTD-3252C9.4 suppressed migration, invasion and proliferation, yet facilitated apoptosis of pancreatic cancer cells both in vitro and in vivo. Then, IFI6 was identified as a downstream target that could be down-regulated by CTD-3252C9.4 and IFI6 overexpression could counteract the effects of CTD-3252C9.4 upregulation on the survival and apoptosis of pancreatic cancer cells. Furthermore, mechanism experiments revealed that IRF1 was a transcriptional factor of IFI6 that can be blocked by CTD-3252C9.4 to inhibit IFI6 transcription. Conclusion Our data indicated that CTD-3252C9.4 could promote pancreatic cancer cell apoptosis and restrain cell growth via binding IRF1 and preventing the transcription of IFI6, which may become a potential therapeutic target for pancreatic cancer.

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Levobupivacaine Induces Ferroptosis by miR-489-3p/SLC7A11 Signaling in Gastric Cancer

Frontiers in Pharmacology ◽

10.3389/fphar.2021.681338 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shun-Hong Mao ◽

Chun-Hua Zhu ◽

Yu Nie ◽

Jian Yu ◽

Lei Wang

Keyword(s):

Gastric Cancer ◽

Cell Growth ◽

Cancer Cells ◽

Cancer Cell ◽

Local Anesthetic ◽

Gastric Cancer Cell ◽

Gastric Cancer Cells ◽

Cancer Cell Growth

Gastric cancer is one of the most the prevalent malignancies and the therapeutic strategies for patients with gastric cancer remains limited. Local anesthetic levobupivacaine has demonstrated potential anti-cancer property, but its correlation with gastric cancer and ferroptosis is poor understood. Here, we identified the novel function of levobupivacaine in regulating ferroptosis of gastric cancer cells. The treatment of levobupivacaine suppressed gastric cancer cell viabilities and Edu-positive cell proportions. The gastric cancer cell growth was reduced by levobupivacaine in vivo. Moreover, the treatment of levobupivacaine enhanced erastin-induced inhibitory impact on gastric cancer cell viabilities. The levels of Fe2+/iron and lipid ROS were induced by levobupivacaine in erastin and RSL3-stimulated gastric cancer cells. levobupivacaine-upregulated miR-489-3p enhanced ferroptosis of gastric cancer cells by targeting SLC7A11. MiR-489-3p was involved in levobupivacaine-induced ferroptosis of gastric cancer cells. Levobupivacaine/miR-489-3p/SLC7A11 axis attenuates gastric cancer cell proliferation in vitro. Therefore, we concluded that the local anesthetic levobupivacaine induced ferroptosis of gastric cancer cells to repress gastric cancer cell growth by miR-489-3p/SLC7A11 axis.

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The O-glycosylation mutant osteopontin alters lung cancer cell growth and migration in vitro and in vivo

International Journal of Molecular Medicine ◽

10.3892/ijmm.2013.1483 ◽

2013 ◽

Vol 32 (5) ◽

pp. 1137-1149 ◽

Cited By ~ 9

Author(s):

ARASH MINAI-TEHRANI ◽

SEUNG-HEE CHANG ◽

SEUNG BUM PARK ◽

MYUNG-HAING CHO

Keyword(s):

Lung Cancer ◽

Cell Growth ◽

Cancer Cell ◽

Lung Cancer Cell ◽

Cancer Cell Growth ◽

Cell Growth And Migration ◽

And Migration

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Novel Pancreatic Cancer Therapy Targeting Cell Surface Glycans by Liposomes Modified with rBC2LCN Lectin

European Surgical Research ◽

10.1159/000513430 ◽

2020 ◽

Vol 61 (4-5) ◽

pp. 113-122

Author(s):

Sota Kimura ◽

Tatsuya Oda ◽

Osamu Shimomura ◽

Tsuyoshi Enomoto ◽

Shinji Hashimoto ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Therapy ◽

Cell Surface ◽

Cancer Cells ◽

Cancer Cell ◽

Human Pancreatic Cancer ◽

Pancreatic Cancer Cells ◽

Cell Surface Glycans

Introduction: Since the outermost layer of cancer cells is covered with various glycans, targeting these groups may serve as an effective strategy in cancer therapy. We previously reported that fucosylated glycans are specifically expressed on pancreatic cancer cells, and that a protein specifically binding to these glycans, namely rBC2LCN lectin, is a potential guiding drug carrier. In the present study, a novel type of glycan-targeting nanoparticle was developed by modifying the surface of doxorubicin-containing liposomes with rBC2LCN lectin. The efficiency and specificity of this formulation, termed Lec-Doxosome, were examined in vitro and in vivo in human pancreatic cancer models. Methods: Lec-Doxosome was prepared by a post-insertion method based on the insertion of rBC2LCN lectin into the liposomal surface via a lipid linker. The in vitro cellular binding, uptake, and cytotoxicity of Lec-Doxosome were compared with the corresponding parameters in the unmodified liposomes by applying to human pancreatic cancer cell line (Capan-1) with affinity for rBC2LCN lectin. For the in vivo assay, Lec-Doxosome was intravenously injected once per week for a total of 3 weeks into mice bearing subcutaneous tumors. Results: The in vitro application of Lec-Doxosome resulted in a 1.2- to 1.6-fold higher intracellular doxorubicin accumulation and a 1.5-fold stronger cytotoxicity compared with the respective rates of accumulation and cytotoxicity in the unmodified liposomes. In vivo, Lec-Doxosome reduced the mean tumor weight (368 mg) compared with that in mice treated with unmodified liposomes (456 mg), without causing any additional adverse events. Conclusion: It was demonstrated from the results obtained herein that rBC2LCN lectin is a potent modifier, as a means for boosting the efficiency of nanoparticles in the targeting of cancer cell surface glycans.

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