Phenformin alone or combined with gefitinib inhibits bladder cancer via AMPK and EGFR pathways

Huang, Yanjun; Zhou, Sichun; He, Caimei; Deng, Jun; Tao, Ting; Su, Qiongli; Darko, Kwame Oteng; Peng, Mei; Yang, Xiaoping

doi:10.1186/s40880-018-0319-7

Cited by 26 publications

(22 citation statements)

References 34 publications

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“…e abnormal glycosylated protein is polyubiquitinated and transferred from the ER into the cytoplasm, and then this abnormal glycosylated PD-L1 gets degraded by proteasome [25]. Consistent with the previous study [11] which showed that the phosphorylation of PD-L1 was associated with ER glycosylation, Chan et al reported that PD-L1 phosphorylation recruits STT3A, an ER-associated glycosyltransferase, to catalyze PD-L1 glycosylation and maintain PD-L1 stability [15]. Hsu and colleagues reported that epithelial-mesenchymal transition (EMT) induced N-glycosyltransferase STT3 through β-catenin, and subsequent STT3-dependent PD-L1 N-glycosylation stabilizes and upregulates PD-L1 [26].…”

Section: Glycosylationsupporting

confidence: 90%

“…Phosphorylation is the most widely studied PTM, and its crosstalk with other PTMs has been significantly proved in recent studies [10]. Metformin activates the AMP-activated protein kinase (AMPK), and then S195 of PD-L1 is directly phosphorylated by p-AMPK, which induces the abnormal glycosylation of PD-L1, leading to its endoplasmic reticulum (ER) accumulation and ER-associated degradation [11]. is process of protein degradation is called endoplasmic reticulum-associated degradation (ERAD) [12].…”

Section: Phosphorylationmentioning

confidence: 99%

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Recent Findings in the Posttranslational Modifications of PD-L1

Zhou

Wang

et al. 2020

Journal of Oncology

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Immune checkpoint therapy, such as the reactivation of T-cell activity by targeting programmed cell death 1 (PD-1) and its ligand PD-L1 (also called B7-H1 and CD274) has been found pivotal in changing the historically dim prognoses of malignant tumors by causing durable objective responses. However, the response rate of immune checkpoint therapy required huge improvements. It has been shown that the expression of PD-L1 on cancer cells and immune cell membranes is correlated with a more durable objective response rate to PD-L1 antibodies, which highlights the importance of deeply understanding how this protein is regulated. Posttranslational modifications such as phosphorylation, N-glycosylation, and ubiquitination of PD-L1 have emerged as important regulatory mechanisms that modulate immunosuppression in patients with cancer. In this review, we summarized the latest findings of PD-L1 protein modification and their clinical applications.

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Section: Glycosylationsupporting

confidence: 90%

Section: Phosphorylationmentioning

confidence: 99%

Recent Findings in the Posttranslational Modifications of PD-L1

Zhou

Wang

et al. 2020

Journal of Oncology

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“…AMPK‐dependent signaling has been shown to mediate the effects of metformin and phenformin on cell growth. In bladder cancer, especially, metformin or phenformin and gefinitib, a well‐known EGFR tyrosine kinase inhibitor, cooperated to inhibit cell growth via AMPK and EGFR pathways . However, this mechanism was not active in our system; indeed, metformin and phenformin did not alter the expression of AMPK‐related molecules (data not shown).…”

Section: Discussionmentioning

confidence: 74%

Effects of metformin and phenformin on apoptosis and epithelial‐mesenchymal transition in chemoresistant rectal cancer

et al. 2019

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Recurrence and chemoresistance in colorectal cancer remain important issues for patients treated with conventional therapeutics. Metformin and phenformin, previously used in the treatment of diabetes, have been shown to have anticancer effects in various cancers, including breast, lung and prostate cancers. However, their molecular mechanisms are still unclear. In this study, we examined the effects of these drugs in chemoresistant rectal cancer cell lines. We found that SW837 and rectal cancer cells were more resistant to ionizing radiation and 5‐fluorouracil than HCT116 and LS513 colon cancer cells. In addition, metformin and phenformin increased the sensitivity of these cell lines by inhibiting cell proliferation, suppressing clonogenic ability and increasing apoptotic cell death in rectal cancer cells. Signal transducer and activator of transcription 3 and transforming growth factor‐β/Smad signaling pathways were more activated in rectal cancer cells, and inhibition of signal transducer and activator of transcription 3 expression using an inhibitor or siRNA sensitized rectal cancer cells to chemoresistant by inhibition of the expression of antiapoptotic proteins, such as X‐linked inhibitor of apoptosis, survivin and cellular inhibitor of apoptosis protein 1. Moreover, metformin and phenformin inhibited cell migration and invasion by suppression of transforming growth factor β receptor 2‐mediated Snail and Twist expression in rectal cancer cells. Therefore, metformin and phenformin may represent a novel strategy for the treatment of chemoresistant rectal cancer by targeting signal transducer and activator of transcription 3 and transforming growth factor‐β/Smad signaling.

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“…Among them, metformin is a potential anti-tumor drug that inhibits hepatic gluconeogenesis and can exert its effects via activation of AMPK [190]. Additionally, the metformin analogue phenformin, alone or in combination with gefitinib, inhibits bladder cancer growth via AMPK activation and EGFR signaling inhibition [191].…”

Section: Glutaminolysismentioning

confidence: 99%

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

Moldogazieva

Mokhosoev

Terentiev

2020

Cancers

110

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It has been long recognized that cancer cells reprogram their metabolism under hypoxia conditions due to a shift from oxidative phosphorylation (OXPHOS) to glycolysis in order to meet elevated requirements in energy and nutrients for proliferation, migration, and survival. However, data accumulated over recent years has increasingly provided evidence that cancer cells can revert from glycolysis to OXPHOS and maintain both reprogrammed and oxidative metabolism, even in the same tumor. This phenomenon, denoted as cancer cell metabolic plasticity or hybrid metabolism, depends on a tumor micro-environment that is highly heterogeneous and influenced by an intensity of vasculature and blood flow, oxygen concentration, and nutrient and energy supply, and requires regulatory interplay between multiple oncogenes, transcription factors, growth factors, and reactive oxygen species (ROS), among others. Hypoxia-inducible factor-1 (HIF-1) and AMP-activated protein kinase (AMPK) represent key modulators of a switch between reprogrammed and oxidative metabolism. The present review focuses on cross-talks between HIF-1, glucose transporters (GLUTs), and AMPK with other regulatory proteins including oncogenes such as c-Myc, p53, and KRAS; growth factor-initiated protein kinase B (PKB)/Akt, phosphatidyl-3-kinase (PI3K), and mTOR signaling pathways; and tumor suppressors such as liver kinase B1 (LKB1) and TSC1 in controlling cancer cell metabolism. The multiple switches between metabolic pathways can underlie chemo-resistance to conventional anti-cancer therapy and should be taken into account in choosing molecular targets to discover novel anti-cancer drugs.

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Phenformin alone or combined with gefitinib inhibits bladder cancer via AMPK and EGFR pathways

Cited by 26 publications

References 34 publications

Recent Findings in the Posttranslational Modifications of PD-L1

Recent Findings in the Posttranslational Modifications of PD-L1

Effects of metformin and phenformin on apoptosis and epithelial‐mesenchymal transition in chemoresistant rectal cancer

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

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