Metformin mediates resensitivity to 5-fluorouracil in hepatocellular carcinoma <i>via</i> the suppression of YAP

Tian, Yu; Tang, Bo; Wang, Cheng‐Ye; Sun, Da; Zhang, Rixin; Luo, Nan; Zhao, Han; Ling, Rui; Gao, Zhenming; Wang, Liming

doi:10.18632/oncotarget.10079

Cited by 48 publications

(35 citation statements)

References 40 publications

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“…Accumulating evidence has confirmed that metformin may inhibit cell migration or potentiate the effect of chemotherapeutic agents (30)(31)(32). Numerous studies have also demonstrated that metformin regulates the AMP-activated protein kinase and extracellular signal-regulated kinase pathways, and reverses drug resistance (33,34).…”

Section: Hif-1α Expression -----------------------------------mentioning

confidence: 99%

Metformin suppresses hypoxia‑induced migration via the HIF‑1α/VEGF pathway in gallbladder cancer in�vitro and in�vivo

Chen

et al. 2018

Oncol Rep

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Hypoxia plays a crucial role in cancer development and progression. Overexpression of hypoxia-inducible factor-1α (HIF-1α) has been demonstrated in a hypoxic microenvironment in various tumor types. Metformin has been identified as an antitumor drug in various tumor types. However, its role in cellular migration in a hypoxic microenvironment, and the associated regulatory mechanism, have yet to be fully elucidated. The present study aimed to investigate the clinical significance of HIF-1α, and its biological role, in gallbladder cancer (GBC). Furthermore, the role of metformin in cellular migration, and its underlying mechanism in GBC, were also identified. Real-time quantitative polymerase chain reaction analysis and immunohistochemistry experiments revealed that HIF-1α was significantly upregulated in GBC tissues. HIF-1α overexpression was closely associated with lymph node metastasis and tumor-lymph node-metastasis (TNM) stages. HIF-1α was able to promote cell migration in a hypoxic microenvironment by overexpressing vascular endothelial growth factor (VEGF) in GBC-SD cells, an effect which was partly reversed by small-interfering RNA HIF-1α (siHIF-1α) and 2-methoxyestradiol. Further experiments demonstrated that metformin inhibited hypoxia-induced migration via HIF-1α/VEGF in vitro. In addition, metformin suppressed GBC growth and downregulated the expression of HIF-1α and VEGF in a GBC-SD cell xenograft model. Taken together, these results suggest that HIF-1α may contribute to tumor migration via the overexpression of VEGF in GBC, while metformin is able to inhibit tumor migration by targeting the HIF-1α/VEGF pathway.

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Section: Hif-1α Expression -----------------------------------mentioning

confidence: 99%

Metformin suppresses hypoxia‑induced migration via the HIF‑1α/VEGF pathway in gallbladder cancer in�vitro and in�vivo

Chen

et al. 2018

Oncol Rep

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“…These characteristics make YAP an attractive therapeutic target in cancer treatment. In HCC, YAP has been revealed to be involved in proliferation, migration, invasion and drug resistance (13)(14)(15). However, the underlying mechanisms remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of YAP inhibits proliferation, invasion and increases cisplatin sensitivity in human hepatocellular carcinoma cells

Wang¹,

Wu²,

Zhong³

2018

Oncol Lett

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Abstract. Yes-associated protein (YAP) serves an essential role in tumorigenesis. However, the potential role and the molecular mechanism underlying the effect of YAP on hepatocellular carcinoma (HCC) cells have not been elucidated. In the current study, it was revealed that YAP expression was increased significantly in HCC cancer tissues and its overexpression was associated with tumor differentiation. The silencing of YAP by small interferring RNA led to the inhibition of HCC cell growth, which was associated with the promotion of apoptosis. The silencing of YAP also decreased the invasive potential of HCC cells and the activity of the phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) signaling pathway. Furthermore, silencing of YAP increased the chemosensitivity of HCC cells to cisplatin (CDDP) through inactivation of the PI3K/AKT signaling pathway. In vivo studies using PDTX model suggested a promotive role for YAP in the growth of HCC and knockdown of YAP increased the anti-tumor activity of CDDP. Taken together, these results revealed that YAP is overexpressed in HCC, and promotes proliferation, invasion and drug resistance of HCC cells. Inhibition of YAP, alone or in combination with traditional chemotherapy, may effectively combat HCC.

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“…Similarly to immune checkpoint inhibitors such as pembrolizumab, metformin has been shown to reverse immune exhaustion . Interestingly, metformin has been shown to potentiate the anticancer effects of other drugs, including antimetabolites and tyrosine kinase inhibitors …”

Section: Discussionmentioning

confidence: 99%

“…70,71 Interestingly, metformin has been shown to potentiate the anticancer effects of other drugs, including antimetabolites and tyrosine kinase inhibitors. 72,73…”

Section: Discussionmentioning

confidence: 99%

Metformin effects on head and neck squamous carcinoma microenvironment: Window of opportunity trial

Curry¹,

Johnson²,

Tassone³

et al. 2017

The Laryngoscope

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Objective The tumor microenvironment frequently displays abnormal cellular metabolism, which contributes to aggressive behavior. Metformin inhibits mitochondrial oxidative phosphorylation, altering metabolism. Though the mechanism is unclear, epidemiologic studies show an association between metformin use and improved outcomes in HNSCC. We sought to determine if metformin alters metabolism and apoptosis in HNSCC tumors. Study Design Window of opportunity trial of metformin between diagnostic biopsy and resection. Participants were patients with newly diagnosed HNSCC. 50 patients were enrolled, and 39 completed a full treatment course. Metformin was titrated to standard diabetic dose (2000 mg/day) for a course of 9 or more days prior to surgery. Level of Evidence 4 Methods Immunohistochemistry (IHC) for the metabolic markers caveolin-1 (CAV1), B-galactosidase (GALB) and monocarboxylate transporter 4 (MCT4) as well as the TUNEL apoptosis assay and Ki-67 IHC were performed in pre- and post-metformin specimens. Exploratory mass spectroscopy imaging (MSI) to assess lactate levels was also performed in three subjects. Results Metformin was well tolerated. The average treatment course was 13.6 days. Post-treatment specimens showed a significant increase in stromal CAV1 (p<0.001) and GALB (p<0.005) and tumor cell apoptosis by TUNEL assay (p<0.001). There was no significant change in stromal MCT4 expression or proliferation measured by Ki67. Lactate levels in carcinoma cells were increased 2.4-fold post-metformin (p<0.05) as measured by MSI. Conclusions Metformin increases markers of reduced catabolism and increased senescence in stromal cells and increased carcinoma cell apoptosis. This study demonstrates that metformin modulates metabolism in the HNSCC microenvironment. Trial Registration ClinicalTrials.gov Identifier NCT02083692.

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Metformin mediates resensitivity to 5-fluorouracil in hepatocellular carcinoma via the suppression of YAP

Cited by 48 publications

References 40 publications

Metformin suppresses hypoxia‑induced migration via the HIF‑1α/VEGF pathway in gallbladder cancer in�vitro and in�vivo

Metformin suppresses hypoxia‑induced migration via the HIF‑1α/VEGF pathway in gallbladder cancer in�vitro and in�vivo

Downregulation of YAP inhibits proliferation, invasion and increases cisplatin sensitivity in human hepatocellular carcinoma cells

Metformin effects on head and neck squamous carcinoma microenvironment: Window of opportunity trial

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