DURATION OF HYPOXIA: EFFECTS ON CELL PROLIFERATION AND CELLULAR CHOLESTEROL LEVELS IN HCT-116 COLON CANCER CELLS
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Abstract
Cancer cells are exposed to a harsh microenvironment that is characterized by oxygen and nutrient deprivation. Hypoxic cancer cells are known to accumulate large quantities of lipids, particularly of triglycerides (TGs). Formation of lipid droplets –that contain triglycerides and cholesterol esters– is a hallmark of hypoxic cancer cells and is positively linked to the ability of cells to survive under oxidative stress. It has been shown that cancer cells have deregulated cholesterol metabolism. Some types of cancer cells have been shown to display increased cholesterol uptake, while others display increased de novo cholesterol synthesis. The effect of hypoxia on cholesterol accumulation has not been investigated in detail. A recent study has shown that hypoxia in combination with serum-deprivation induces overall decrease in cholesterol ester levels in colon and lung cancer cell. However, hypoxia (48hrs) alone was not able to induce any changes. It has been speculated that increasing the duration of hypoxia may have some impact on cholesterol accumulation in cancer cells. The presented work aimed to study the impact of varying durations of hypoxia on cholesterol content and cell proliferation rates in cancer cells. It was observed that cholesterol-load was slightly decreased after 48hours of hypoxia however this difference did not reach statistical significance. After 72 hour of hypoxia the cholesterol-load was same as under normoxic conditions. The cellular lipid-load was also assessed by Oil Red-O (ORO) staining which showed no visible differences between normoxic and hypoxic cells. To assess the underlying molecular mechanism the expression of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) –the rate- limiting enzyme of mevalonate pathway– was also assessed. Again no significant difference was observed in HMGCR expression between normoxic and hypoxic cells. Further studies are required to understand the hypoxic regulation of cholesterol metabolism in cancer cells.
References
2. Brown, J.M. and A.J. Giaccia, The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res, 1998. 58(7): p. 1408-16.
3. Hanahan, D. and R.A. Weinberg, Hallmarks of cancer: the next generation. Cell, 2011. 144(5): p. 646-74.
4. Masson, N. and P.J. Ratcliffe, Hypoxia signaling pathways in cancer metabolism: the importance of co-selecting interconnected physiological pathways. Cancer Metab, 2014. 2(1): p. 2049-3002.
5. Rankin, E.B. and A.J. Giaccia, Hypoxic control of metastasis. Science, 2016. 352(6282): p. 175-80.
6. Gutierrez-Pajares, J.L., et al., SR-BI: Linking Cholesterol and Lipoprotein Metabolism with Breast and Prostate Cancer. Front Pharmacol, 2016. 7(338).
7. Usman, H., et al., Leukemia cells display lower levels of intracellular cholesterol irrespective of the exogenous cholesterol availability. Clin Chim Acta, 2016. 457: p. 12-7.
8. Brusselmans, K., et al., Squalene synthase, a determinant of Raft-associated cholesterol and modulator of cancer cell proliferation. J Biol Chem, 2007. 282(26): p. 18777-85.
9. Freeman, M.R., D. Di Vizio, and K.R. Solomon, The Rafts of the Medusa: cholesterol targeting in cancer therapy. Oncogene, 2010. 29(26): p. 3745-7.
10. Davidson, M.H., Safety profiles for the HMG-CoA reductase inhibitors: treatment and trust. Drugs, 2001. 61(2): p. 197-206.
11. Larsson, O., HMG-CoA reductase inhibitors: role in normal and malignant cells. Crit Rev Oncol Hematol, 1996. 22(3): p. 197-212.
12. Huang, D., et al., HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression. Cell reports, 2014. 8(6): p. 1930-1942.
13. Zaidi, N., et al., Lipogenesis and lipolysis: the pathways exploited by the cancer cells to acquire fatty acids. Prog Lipid Res, 2013. 52(4): p. 585-9.
14. Lisec, J., C. Jaeger, and N. Zaidi, Cancer cell lipid class homeostasis is altered under nutrient-deprivation but stable under hypoxia. 2018: p. 382457.
15. Zhang, X., et al., Inhibition of intracellular lipolysis promotes human cancer cell adaptation to hypoxia. Elife, 2017. 19(6): p. 31132.
16. Guillaumond, F., et al., Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma. Proc Natl Acad Sci U S A, 2015. 112(8): p. 2473-8.
17. Kamphorst, J.J., et al., Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc Natl Acad Sci U S A, 2013. 110(22): p. 8882-7.
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Najeeha Javed
University of Punjab, Quaid-e-Azam Campus, Lahore , Pakistan
Dr Nousheen Zara Zaidi
Johnson Johnson, Germany & University of Punjab, Quaid-e-Azam campus Lahore, Pakistan
Dr Fatima Majeed
University of punjab Quaid azam campus Lahore Pakistan
Dr Asad Latif
Services Institute of Medical Sciences Lahore, Pakistan
Ferheen Shahbaz
Department of Public Health, University of The Punjab. Lahore, Pakistan
Dr. Hannan Arif
Punjab Rangers Teaching Hospital, Lahore, Punjab, Pakistan