High Glucose Accelerates Tumor Progression by Regulating MEDAG-Mediated Autophagy Levels in Breast Cancer

Abstract

Recent studies have shown that diabetes is a major risk factor for breast cancer (BC), but the mechanism is incompletely understood. Mesenteric estrogen-dependent adipogenesis (MEDAG) plays a significant role in both glucose uptake and BC development. However, the relationship between MEDAG and BC under high glucose (HG) conditions remains unclear. In our study, MEDAG expression was higher in BC tissue from diabetic patients than in BC tissue from nondiabetic patients. HG promoted BC progression in vitro and in vivo by upregulating MEDAG expression. Furthermore, MEDAG deficiency increased the autophagosome number and autophagic flux. Moreover, inhibition of autophagy partially reversed MEDAG knockdown (MEDAG KD )-induced suppression of tumorigenic biological behaviors and epithelial-mesenchymal transition (EMT) progression. Finally, MEDAG significantly suppressed AMPK phosphorylation. Additionally, the AMPK inhibitor Compound C markedly reduced autophagosome accumulation and antitumor effects in MEDAG KD cells. Treatment with the AMPK activator AICAR exhibited similar effects in MEDAG-overexpressing (MEDAG OE ) cells. In conclusion, the MEDAG-AMPK-autophagy axis is vital to BC progression in diabetic patients. Our findings provide a novel treatment target for BC in patients with diabetes.

High glucose inhibits autophagy and promotes the proliferation and metastasis of colorectal cancer through the PI3K/AKT/mTOR pathway

“…Chenyuan Li found that high glucose promoted breast cancer progression both in vitro and in vivo by upregulating MEDAG expression. Furthermore, MEDAG deficiency led to an increase in the number of autophagosomes and autophagic flux 25 . Therefore, autophagy and EMT have such a regulatory relationship in various cancers; the prospect of utilizing autophagy to regulate the EMT process and consequently control tumor metastasis represents a promising discovery.…”

“…[20][21][22][23][24] mTOR is the central checkpoint that negatively regulates autophagy, and anti-cancer drugs weaken the PI3K/AKT/ mTOR pathway to stimulate autophagy. High-glucose levels have been shown to promote the proliferation of various types of tumors, such as breast cancer, 25 CRC, 26 lung cancer, 27 and liver cancer. 28 Tumor cells exposed to high glucose exhibit intracellular signaling alterations that lead to a more aggressive phenotype.…”

Metabolic Profile and Negatively Association Between Insulin Resistance and Metastatic Incidence in Indonesian Primary Invasive Breast Cancer: A Cross-Sectional Study

“…29 In breast cancer patients, heightened blood glucose levels will impinge on the cancer progressivity and staging via different pathways. [30][31][32] Regarding aromatase inhibitors, administration of the drug was identified to impact visceral adiposity and glucose metabolism due to its mechanism of action. 33,34 Metabolic disturbance due to obesity impairs insulin sensitivity, and most obese people were ascertained to have at least one afflicted metabolism and insulin sensitivity parameters.…”

Role of Escin in breast cancer therapy: potential mechanism for inducing ferroptosis and synergistic antitumor activity with cisplatin

“…The procedure was carried out according to our previous study [ 34 ]. In brief, treated cells were fixed with ice-cold 2.5% glutaraldehyde at 4 °C for 1 h. Then, the cells were collected and centrifuged at 800 rpm for 5 min.…”

“…The procedure and the scoring rules were performed according to our previous study [ 34 ]. Antibodies against G6PD (1:100, Proteintech, 25413-1-AP) and GPX4 (1:100, Proteintech, 67763-1-Ig) were used.…”