Aspirin inhibits the proliferation of hepatoma cells through controlling GLUT1-mediated glucose metabolism

Abstract

Aspirin can efficiently inhibit liver cancer growth, but the mechanism is poorly understood. In this study, we report that aspirin modulates glucose uptake through downregulating glucose transporter 1 (GLUT1), leading to the inhibition of hepatoma cell proliferation. Our data showed that aspirin significantly decreased the levels of reactive oxygen species (ROS) and glucose consumption in hepatoma cells. Interestingly, we identified that GLUT1 and HIF1α could be decreased by aspirin. Mechanically, we demonstrated that the -1008/-780 region was the regulatory element of transcriptional factor NF-κB in GLUT1 promoter by luciferase report gene assays. PDTC, an inhibitor of NF-κB, could suppress the expression of GLUT1 in HepG2 and H7402 cells, followed by affecting the levels of ROS and glucose consumption. CoCl-activated HIF1α expression could slightly rescue the GLUT1 expression inhibited by aspirin or PDTC, suggesting that aspirin depressed GLUT1 through targeting NF-κB or NF-κB/HIF1α signaling. Moreover, we found that GLUT1 was highly expressed in clinical HCC tissues relating to their paired adjacent normal tissues. Importantly, we observed that high level of GLUT1 was significantly correlated with the poor relapse-free survival of HCC patients by analysis of public data. Functionally, overexpression of GLUT1 blocked the PDTC-induced or aspirin-induced inhibition of glucose metabolism in HepG2 cells. Conversely, aspirin failed to work when GLUT1 was stably knocked down in the cells. Administration of aspirin could depress the growth of hepatoma cells through controlling GLUT1 in vitro and in vivo. Thus, our finding provides new insights into the mechanism by which aspirin depresses liver cancer.

Glucose Metabolism on Tumor Plasticity, Diagnosis, and Treatment

“…Dalton's lymphoma (T-cell lymphoma) cells obtained from tumor-bearing mice treated by aspirin showed a change of expression of pH regulators MCT-1 and V-ATPase, as well as change in cell survival regulatory molecules including GLUT-1 (131). Aspirin can also modulate glucose uptake by depressing GLUT-1 through targeting NF-κB or NF κB/HIF1α signaling to inhibit proliferation (132).…”

Untargeted Metabolomics to Go beyond the Canonical Effect of Acetylsalicylic Acid

“…This effect of ASA is currently explained by its ability to acetylate proteins other than COX-1 [38]. Recently, it has been demonstrated that ASA also decreases the expression of the hypoxia-inducible factor 1alpha (HIF1α), a key regulator of genes that are involved in metabolism under hypoxic conditions and a major determinant of tumor cell stabilization [39,40]. In a recent report [41], it has been shown that under normoxic conditions, HIF1α activity is significantly increased by glutamine metabolism, and is decreased by (a) acetylation via acetyl CoA synthetase or ATP citrate lyase, and (b) the presence of L-ascorbic acid, citrate, or acetyl-CoA.…”

Terahertz polarization sensing based on metasurface microsensor display anti-proliferation of tumor cells with aspirin

“…Aspirin (Sigma-Aldrich, St. Louis, MO, USA) was dissolved in dimethyl sulfoxide (DMSO) (Sigma-Aldrich, St. Louis, MO, USA). Given that the aspirin treatment mainly referred to the previous studies in HEK293T cells [35], HepG2 cells [36,37] and B16 cells [38], 2.5 mM aspirin was added into HEK293T, HepG2 and B16 cells for 48 h. After aspirin treatment for 48 h, cells were collected after trypsin digestion and low-speed centrifugation (800 rpm, 5 min). To exclude the effect of residual drugs, cells were washed twice using phosphate buffer saline.…”