The Role of 5' Adenosine Monophosphate-Activated Protein Kinase in the Chemo-Sensitivity and Metabolic Behaviour of Breast Cancer Cells Exposed to Hypoxia and Hyperglycaemia
DOI:
https://doi.org/10.30683/1929-2279.2022.11.02Keywords:
AMPK, hyperglycaemia, hypoxia, insulin-like growth factor binding protein 2, chemo-resistance, fatty acid synthaseAbstract
Background: 5' adenosine monophosphate-activated protein kinase (AMPK) is a key enzyme for maintaining energy homeostasis in the cell and is associated with many downstream targets of metabolic processes such as mTORC1, p53 and fatty acid synthase (FASN) and insulin-like growth factor binding protein-2 (IGFBP-2).
Aim: To investigate the interactions between AMPK, FASN and IGFBP-2 and how the activity of AMPK affects the metabolism and response of breast cancer cells to chemotherapy with changes in oxygenation and under different glucose concentrations.
Methods: MCF-7 breast cancer cells were exposed to different glucose levels (5mM and 25mM) in the presence or absence of doxorubicin under normoxic and hypoxic conditions with and without AMPK silenced using siRNA. Changes in protein abundance were monitored using Western Immunoblotting. Cell death was measured by the Muse® Cell Analyser using a count and viability assay. Hypoxia was chemically induced using cobalt chloride or with low levels of oxygen (2%). Lactate and citrate levels were measured using commercially available kits.
Results: In normoxic conditions, AMPK activity was higher in normal levels of glucose (5mM) compared with high levels of glucose (25mM). Under hypoxic conditions, AMPK phosphorylation remained high in 5mM glucose with levels in 25 mM glucose being equivalent. Upregulation of AMPK in normoxic and hypoxic conditions was associated with a reduction in FASN and IGFBP-2, which resulted in a better response to chemotherapy. Moreover, the cells increased the production of lactate and reduced production of citrate under normoxic conditions in 25mM glucose compared to 5mM glucose. Silencing AMPK under normoxic conditions or inducing hypoxia promoted a more glycogenic phenotype. However, silencing AMPK under hypoxic conditions reduced levels of lactate comparable to normoxic levels. The citrate profile was unaffected by silencing AMPK or altering levels of oxygen.
Conclusions: AMPK plays an important role in regulating metabolic signalling and this alters the sensitivity of breast cancer cells to chemotherapy.
References
Lee AH, et al. Inflammatory infiltrate in invasive lobular and ductal carcinoma of the breast. Br J Cancer 1996; 74(5): 796-801. https://doi.org/10.1038/bjc.1996.438
Pouyssegur J, et al. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 2006; 441(7092): 437-43. https://doi.org/10.1038/nature04871
Steinberg GR, Kemp BE. AMPK in Health and Disease. Physiol Rev 2009; 89(3): 1025-78. https://doi.org/10.1152/physrev.00011.2008
Ruderman N, Prentki M. AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat Rev Drug Discov 2004; 3(4): 340- 51. https://doi.org/10.1038/nrd1344
Luo Z, et al. AMPK, the metabolic syndrome and cancer. Trends Pharmacol Sci 2005; 26(2): 69-76. https://doi.org/10.1016/j.tips.2004.12.011
Hoyer-Hansen M, Jaattela M. AMP-activated protein kinase: a universal regulator of autophagy? Autophagy 2007; 3(4): 381-3. https://doi.org/10.4161/auto.4240
Jansen M, et al. LKB1 and AMPK family signaling: the intimate link between cell polarity and energy metabolism. Physiol Rev 2009; 89(3): 777-98. https://doi.org/10.1152/physrev.00026.2008
Luo Z, et al. AMPK as a metabolic tumor suppressor: control of metabolism and cell growth. Future Oncol 2010; 6(3): 457-70. https://doi.org/10.2217/fon.09.174
Zeng L, et al. Hyperglycaemia confers resistance to chemotherapy on breast cancer cells: the role of fatty acid synthase. Endocr Relat Cancer 2010; 17(2): 539-51. https://doi.org/10.1677/ERC-09-0221
Al Qahtani A, et al. Hypoxia negates hyperglycaemia-induced chemo-resistance in breast cancer cells: the role of insulin-like growth factor binding protein 2. Oncotarget 2017; 8(43): 74635-74648. https://doi.org/10.18632/oncotarget.20287
Biernacka KM, et al. Hyperglycaemia-induced chemoresistance of prostate cancer cells due to IGFBP2. Endocr Relat Cancer 2013; 20(5): 741-51. https://doi.org/10.1530/ERC-13-0077
Lopez M, et al. Hypothalamic AMPK: a canonical regulator of whole-body energy balance. Nat Rev Endocrinol 2016; 12(7): 421-32. https://doi.org/10.1038/nrendo.2016.67
Huang Z, et al. ALOX12 inhibition sensitizes breast cancer to chemotherapy via AMPK activation and inhibition of lipid synthesis. Biochem Biophys Res Commun 2019; 514(1): 24-30. https://doi.org/10.1016/j.bbrc.2019.04.101
Wei C, et al. Cordycepin Inhibits Drug-resistance Non-small Cell Lung Cancer Progression by Activating AMPK Signaling Pathway. Pharmacol Res 2019; 144: 79-89. https://doi.org/10.1016/j.phrs.2019.03.011
Huang M, et al. Diet-induced alteration of fatty acid synthase in prostate cancer progression. Oncogenesis 2016; 5: e195. https://doi.org/10.1038/oncsis.2015.42
Warburg O. On respiratory impairment in cancer cells. Science 1956; 124(3215): 269-70. https://doi.org/10.1126/science.124.3215.269
Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell 2008; 13(6): 472-82. https://doi.org/10.1016/j.ccr.2008.05.005
Gogvadze V, et al. Mitochondria in cancer cells: what is so special about them? Trends Cell Biol 2008; 18(4): 165-73. https://doi.org/10.1016/j.tcb.2008.01.006
Jia D, et al. Elucidating cancer metabolic plasticity by coupling gene regulation with metabolic pathways. Proc Natl Acad Sci 2019; 116(9): 3909-3918. https://doi.org/10.1073/pnas.1816391116
De Saedeleer CJ, et al. Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells. PLoS One 2012; 7(10): e46571. https://doi.org/10.1371/journal.pone.0046571
Linglin Y, et al. Modeling the Genetic Regulation of Cancer Metabolism: Interplay between Glycolysis and Oxidative Phosphorylation. Cancer Res 2017; 77(7); 1564-74. https://doi.org/10.1158/0008-5472.CAN-16-2074
Faubert B, Boily G, et al. AMPK is a negative regulator of the Warburg Effect and suppresses tumor growth in vivo. Cell Metab 2013; 17(1): 113-124. https://doi.org/10.1016/j.cmet.2012.12.001
Kennedy KM, et al. Catabolism of Exogenous Lactate Reveals It as a Legitimate Metabolic Substrate in Breast Cancer. PLoS One 2013; 8(9): 20. https://doi.org/10.1371/journal.pone.0075154
Brunello A, et al. Hyperglycemia during chemotherapy for hematologic and solid tumors is correlated with increased toxicity. Am J Clin Oncol 2011; 34(3): 292-6. https://doi.org/10.1097/COC.0b013e3181e1d0c0
Rizos C, Elisaf M. Metformin and cancer. Eur J Pharmacol 2013; 705: 96-108. https://doi.org/10.1016/j.ejphar.2013.02.038
Bost F, et al. Metformin and cancer therapy. Curr Opin Oncol 2012; 24: 103-108. https://doi.org/10.1097/CCO.0b013e32834d8155
Donadon V, et al. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients with chronic liver disease. Liver Int 2010; 30: 750-758. https://doi.org/10.1111/j.1478-3231.2010.02223.x
Donadon V, et al. Glycated hemoglobin and antidiabetic strategies as risk factors for hepatocellular carcinoma. World J Gastroenterol 2010; 16: 3025-3032. https://doi.org/10.3748/wjg.v16.i24.3025
Klubo-Gwiezdzinska J, et al. Treatment with metformin is associated with higher remission rate in diabetic patients with thyroid cancer. J Clin Endocrinol Metab 2013; 98: 3269-3279. https://doi.org/10.1210/jc.2012-3799
Kumar S, et al. Metformin intake is associated with better survival in ovarian cancer: A case-control study. Cancer 2013; 119: 555-562. https://doi.org/10.1002/cncr.27706
Romero I, et al. Relationship of type II diabetes and metformin use to ovarian cancer progression, survival, and chemosensitivity. Obstet Gynecol 2012; 119: 61-67. https://doi.org/10.1097/AOG.0b013e3182393ab3
Gallagher E, LeRoith D. The proliferating role of insulin and insulin-like growth factors in cancer. Trends Endocrinol Metab 2010; 21: 610-618. https://doi.org/10.1016/j.tem.2010.06.007
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