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Differential effects of AMPK agonists on cell growth and metabolism
E E Vincent1, P P Coelho1, J Blagih1
11] Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada [2] Department of Physiology, McGill University, Montreal, Quebec, Canada.
Abstract:
As a sensor of cellular energy status, the AMP-activated protein kinase (AMPK) is believed to act in opposition to the metabolic phenotypes favored by proliferating tumor cells. Consequently, compounds known to activate AMPK have been proposed as cancer therapeutics. However, the extent to which the anti-neoplastic properties of these agonists are mediated by AMPK is unclear. Here we examined the AMPK dependence of six commonly used AMPK agonists (metformin, phenformin, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), 2-deoxy-D-glucose (2DG), salicylate and A-769662) and their influence on cellular processes often deregulated in tumor cells. We demonstrate that the majority of these agonists display AMPK-independent effects on cell proliferation and metabolism with only the synthetic activator, A-769662, exerting AMPK-dependent effects on these processes. We find that A-769662 promotes an AMPK-dependent increase in mitochondrial spare respiratory capacity. Finally, contrary to the view of AMPK activity being tumor suppressive, we find that A-769662 confers a selective proliferative advantage to tumor cells growing under nutrient deprivation. Our results indicate that many of the antigrowth properties of these agonists cannot be attributed to AMPK activity in cells, and thus any observed effects using these agonists should be confirmed using AMPK-deficient cells. Ultimately, our data urge caution not only regarding the type of AMPK agonist proposed for cancer treatment but also the context in which they are used.
Insights
Many AMP-activated protein kinase (AMPK) activators used in cancer research have AMPK-independent effects on tumor cells. Only A-769662 showed AMPK-dependent anti-cancer properties, but it also promoted tumor growth in nutrient-poor conditions.
Area of Science:
- Cellular metabolism
- Cancer biology
- Pharmacology
Background:
- AMP-activated protein kinase (AMPK) regulates cellular energy and is a target for cancer therapeutics.
- Tumor cells often exhibit metabolic phenotypes counter to AMPK activity.
- The precise role of AMPK in mediating the anti-cancer effects of its agonists is not fully understood.
Purpose of the Study:
- To investigate the AMPK dependence of commonly used AMPK agonists on cancer cell proliferation and metabolism.
- To determine the influence of these agonists on cellular processes deregulated in tumors.
- To clarify the therapeutic potential and context-specific effects of AMPK agonists in cancer.
Main Methods:
- Tested six AMPK agonists (metformin, phenformin, AICAR, 2DG, salicylate, A-769662) for their effects on cell proliferation and metabolism.
- Assessed the AMPK dependence of these effects.
- Examined the impact of A-769662 on mitochondrial respiratory capacity.
- Evaluated tumor cell growth under nutrient deprivation.
Main Results:
- Most tested agonists exhibited AMPK-independent effects on cell proliferation and metabolism.
- Only A-769662 demonstrated AMPK-dependent effects on these processes.
- A-769662 increased mitochondrial spare respiratory capacity in an AMPK-dependent manner.
- Contrary to expectations, A-769662 conferred a proliferative advantage to tumor cells under nutrient deprivation.
Conclusions:
- The anti-proliferative effects of many AMPK agonists are not mediated by AMPK.
- A-769662's effects are AMPK-dependent, but it can paradoxically promote tumor growth in specific conditions.
- Results necessitate caution in selecting AMPK agonists and considering their usage context for cancer therapy.
- Future studies should validate findings in AMPK-deficient cells and consider the tumor microenvironment.
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