Glucagon-like peptide-1 receptor activation by liraglutide promotes breast cancer through NOX4/ROS/VEGF pathway

Liu, Zhanzhao; Duan, Xianxian; Yuan, Mengci; Yu, Jing; Hu, Xiao; Han, Xiao; Lan, Lan; Liu, Bowei; Wang, Yue; Qin, Jianjie

doi:10.1016/j.lfs.2022.120370

Cited by 12 publications

(11 citation statements)

References 46 publications

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“…Cytochrome P450 family 2 subfamily E member 1 ( cyp2e1 ) is linked to insulin resistance and oxidative stress, contributing to non-alcoholic fatty liver disease [ 44 ], a condition with established associations to increased BC risk [ 45 ]. Glucagon-like peptide 1 receptor ( glp1r ), the receptor for glp1, sees elevated expression following diabetes treatment with GLP1 and its analogs, potentially promoting BC malignancy [ 46 , 47 ]. Epidermal growth factor receptor ( egfr ), a member of the erbb family, plays a critical role in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Reversal of tamoxifen resistance by artemisinin in ER+ breast cancer: bioinformatics analysis and experimental validation

ZHUO,

ZHANG,

et al. 2024

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Breast cancer is the leading cause of cancer-related deaths in women worldwide, with Hormone Receptor (HR)+ being the predominant subtype. Tamoxifen (TAM) serves as the primary treatment for HR+ breast cancer. However, drug resistance often leads to recurrence, underscoring the need to develop new therapies to enhance patient quality of life and reduce recurrence rates. Artemisinin (ART) has demonstrated efficacy in inhibiting the growth of drug-resistant cells, positioning art as a viable option for counteracting endocrine resistance. This study explored the interaction between artemisinin and tamoxifen through a combined approach of bioinformatics analysis and experimental validation. Five characterized genes ( ar, cdkn1a, erbb2, esr1, hsp90aa1 ) and seven drug-disease crossover genes ( cyp2e1, rorc, mapk10, glp1r, egfr, pgr, mgll ) were identified using WGCNA crossover analysis. Subsequent functional enrichment analyses were conducted. Our findings confirm a significant correlation between key cluster gene expression and immune cell infiltration in tamoxifen-resistant and -sensitized patients. scRNA-seq analysis revealed high expression of key cluster genes in epithelial cells, suggesting artemisinin’s specific impact on tumor cells in estrogen receptor (ER)-positive BC tissues. Molecular target docking and in vitro experiments with artemisinin on LCC9 cells demonstrated a reversal effect in reducing migratory and drug resistance of drug-resistant cells by modulating relevant drug resistance genes. These results indicate that artemisinin could potentially reverse tamoxifen resistance in ER-positive breast cancer.

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Section: Discussionmentioning

confidence: 99%

Reversal of tamoxifen resistance by artemisinin in ER+ breast cancer: bioinformatics analysis and experimental validation

ZHUO,

ZHANG,

et al. 2024

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“…We found that liraglutide treatment improved the migration and tube formation of HG-treated EPC in a dose-dependent manner ( Figure 3 A–D), while GLP-1R antagonist exendin abolished these protective effects ( Figure 3 E–H), demonstrating that liraglutide directly improves the function of diabetic EPC in addition to its effects of lowering blood glucose and body weight. Besides that, liraglutide may also preserve the angiogenic signals, such as VEGF [ 37 ] and subsequently improve the function of diabetic EPC.…”

Section: Discussionmentioning

confidence: 99%

Liraglutide Improves the Angiogenic Capability of EPC and Promotes Ischemic Angiogenesis in Mice under Diabetic Conditions through an Nrf2-Dependent Mechanism

Yan

Xia

et al. 2022

Cells

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The impairment in endothelial progenitor cell (EPC) functions results in dysregulation of vascular homeostasis and dysfunction of the endothelium under diabetic conditions. Improving EPC function has been considered as a promising strategy for ameliorating diabetic vascular complications. Liraglutide has been widely used as a therapeutic agent for diabetes. However, the effects and mechanisms of liraglutide on EPC dysfunction remain unclear. The capability of liraglutide in promoting blood perfusion and angiogenesis under diabetic conditions was evaluated in the hind limb ischemia model of diabetic mice. The effect of liraglutide on the angiogenic function of EPC was evaluated by cell scratch recovery assay, tube formation assay, and nitric oxide production. RNA sequencing was performed to assess the underlying mechanisms. Liraglutide enhanced blood perfusion and angiogenesis in the ischemic hindlimb of db/db mice and streptozotocin-induced type 1 diabetic mice. Additionally, liraglutide improved tube formation, cell migration, and nitric oxide production of high glucose (HG)-treated EPC. Assessment of liraglutide target pathways revealed a network of genes involved in antioxidant activity. Further mechanism study showed that liraglutide decreased the production of reactive oxygen species and increased the activity of nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 deficiency attenuated the beneficial effects of liraglutide on improving EPC function and promoting ischemic angiogenesis under diabetic conditions. Moreover, liraglutide activates Nrf2 through an AKT/GSK3β/Fyn pathway, and inhibiting this pathway abolished liraglutide-induced Nrf2 activation and EPC function improvement. Overall, these results suggest that Liraglutide represents therapeutic potential in promoting EPC function and ameliorating ischemic angiogenesis under diabetic conditions, and these beneficial effects relied on Nrf2 activation.

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“…Furthermore, liraglutide promoted weight reduction, improved angiogenesis in adipose tissue, and alleviated the deleterious effects of aberrant, unhealthy adipose tissue remodeling and metabolic disturbance [334]. There are concerns that liraglutide may promote malignant progression in human triple-negative breast cancer through NADPH oxidase 4 (NOX4) and ROS/VEGF signaling pathways after activating the GLP-1 receptor [335]. However, a recent meta-analysis indicated that liraglutide and other GLP-1 agonists are not associated with an increased risk of breast cancer [336].…”

Section: Incretin-based Therapiesmentioning

confidence: 99%

Atherosclerosis, Diabetes Mellitus, and Cancer: Common Epidemiology, Shared Mechanisms, and Future Management

Katsi

Papakonstantinou

Tsioufis

2023

IJMS

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The involvement of cardiovascular disease in cancer onset and development represents a contemporary interest in basic science. It has been recognized, from the most recent research, that metabolic syndrome-related conditions, ranging from atherosclerosis to diabetes, elicit many pathways regulating lipid metabolism and lipid signaling that are also linked to the same framework of multiple potential mechanisms for inducing cancer. Otherwise, dyslipidemia and endothelial cell dysfunction in atherosclerosis may present common or even interdependent changes, similar to oncogenic molecules elevated in many forms of cancer. However, whether endothelial cell dysfunction in atherosclerotic disease provides signals that promote the pre-clinical onset and proliferation of malignant cells is an issue that requires further understanding, even though more questions are presented with every answer. Here, we highlight the molecular mechanisms that point to a causal link between lipid metabolism and glucose homeostasis in metabolic syndrome-related atherosclerotic disease with the development of cancer. The knowledge of these breakthrough mechanisms may pave the way for the application of new therapeutic targets and for implementing interventions in clinical practice.

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Glucagon-like peptide-1 receptor activation by liraglutide promotes breast cancer through NOX4/ROS/VEGF pathway

Cited by 12 publications

References 46 publications

Reversal of tamoxifen resistance by artemisinin in ER+ breast cancer: bioinformatics analysis and experimental validation

Reversal of tamoxifen resistance by artemisinin in ER+ breast cancer: bioinformatics analysis and experimental validation

Liraglutide Improves the Angiogenic Capability of EPC and Promotes Ischemic Angiogenesis in Mice under Diabetic Conditions through an Nrf2-Dependent Mechanism

Atherosclerosis, Diabetes Mellitus, and Cancer: Common Epidemiology, Shared Mechanisms, and Future Management

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