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Exploring the Anticancer Potential of Astragalin in Triple Negative Breast Cancer Cells by Attenuating Glycolytic
Ahmad Zeb1,2, Walizeb Khan1, Waseem Ul Islam3,4
1Department of Biosciences, COMSATS University, Islamabad, 45550, Pakistan.
Background:
Aerobic glycolysis is crucial for cancer cells to survive, grow, and progress. In the current study, the anti-cancer effects of astragalin (ASG) on breast cancer cells and in the glycolytic pathway through AMPK/mTOR have been evaluated.
Objective:
The objective of this study was to examine the impact of ASG, a natural flavonoid, on glycolysis via targeting AMPK/mTOR signalling in MDA-MB-231 breast cancer cells.
Methods:
The study utilized ASG, which was isolated from Haplophyllum tuberculatum. The cells were treated with different concentrations of ASG (20 and 40 μg/mL), and anti-glycolytic activities were measured through cell proliferation, expression of glycolytic enzymes (HK-2, LDH-A, GLUT-1), glucose uptake, and lactate concentration assays. The MTT assay was used to assess cellular proliferation, while the glucose uptake and lactate levels were determined by employing colorimetric assays. The mRNA expression of target glycolytic enzymes was determined by qRT-PCR. The protein levels of glycolytic targets, as well as that of AMPK and mTOR, were determined by western blot. in silico docking of ASG was done with mTOR and AMPK proteins.
Results:
Astragalin exhibited dose- and time-dependent anti-proliferative effects in MDA-MB-231 cells. In breast cancer cells, the mRNA and protein expression of GLUT-1, LDH-A, and HK-2 were all significantly downregulated after receiving ASG treatments. Furthermore, after ASG treatments, MDA-MB231 cells showed a significant decrease in lactate and glucose uptake compared to control cells. Mechanistically, ASG increased AMPK activation and suppressed mTOR activation in these cells. The inhibitory role of ASG on aerobic glycolysis was prevented by treatments with compound C (an AMPK inhibitor). However, combined treatment of compound C and ASG could nullify the ASG-induced anti-glycolysis effect and restore the level of p-AMPK and p-mTOR in MDA-MB231 cells. The results from molecular docking predicted that ASG had the potential to bind AMPK and mTOR, with free energy for binding, -8.2 kcal/mol and -8.1 kcal/mol, respectively.
Conclusion:
Taken together, the findings from this study indicated that ASG might modulate the AMPK/mTOR pathway to inhibit aerobic glycolysis and proliferation of MDAMB231 breast cancer.
Insights
Astragalin (ASG) inhibits breast cancer cell proliferation by targeting aerobic glycolysis. ASG downregulates key glycolytic enzymes and glucose uptake, mediated through the AMPK/mTOR pathway.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Aerobic glycolysis is essential for cancer cell survival and progression.
- Targeting the glycolytic pathway presents a therapeutic strategy for cancer treatment.
Purpose of the Study:
- To investigate the anti-cancer effects of astragalin (ASG) on breast cancer cells.
- To elucidate the mechanism of ASG's action on the glycolytic pathway via the AMPK/mTOR signaling cascade.
Main Methods:
- ASG isolated from Haplophyllum tuberculatum was used to treat MDA-MB-231 breast cancer cells.
- Assays included MTT for proliferation, colorimetric assays for glucose uptake and lactate, qRT-PCR for mRNA expression of glycolytic enzymes (HK-2, LDH-A, GLUT-1), and western blot for protein levels.
- In silico molecular docking was performed for ASG with AMPK and mTOR proteins.
Main Results:
- ASG demonstrated dose- and time-dependent anti-proliferative effects on MDA-MB-231 cells.
- ASG significantly downregulated mRNA and protein expression of GLUT-1, LDH-A, and HK-2, reducing glucose uptake and lactate production.
- ASG activated AMPK and inhibited mTOR, with these effects reversed by an AMPK inhibitor (Compound C). Molecular docking indicated ASG binds to AMPK and mTOR.
Conclusions:
- Astragalin inhibits aerobic glycolysis and proliferation in MDA-MB-231 breast cancer cells.
- The mechanism involves modulation of the AMPK/mTOR pathway.
- ASG shows potential as an anti-cancer agent targeting glycolysis.
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