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Extracellular Fatty Acids Are the Major Contributor to Lipid Synthesis in Prostate Cancer

Balaban, Seher, Nassar, Zeyad D., Zhang, Alison Y., Hosseini-Beheshti, Elham, Centenera, Margaret M., Schreuder, Mark, Lin, Hui-Ming, Aishah, Atqiya, Varney, Bianca, Liu-Fu, Frank, Lee, Lisa S., Nagarajan, Shilpa R., Shearer, Robert F., Hardie, Rae-Anne, Raftopulos, Nikki L., Kakani, Meghna S., Saunders, Darren N., Holst, Jeff, Horvath, Lisa G., Butler, Lisa M., Hoy, Andrew J.·2019·Molecular Cancer Research
DOI 10.1158/1541-7786.mcr-18-0347

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Abstract

Prostate cancer cells exhibit altered cellular metabolism but, notably, not the hallmarks of Warburg metabolism. Prostate cancer cells exhibit increased de novo synthesis of fatty acids (FA); however, little is known about how extracellular FAs, such as those in the circulation, may support prostate cancer progression. Here, we show that increasing FA availability increased intracellular triacylglycerol content in cultured patient-derived tumor explants, LNCaP and C4-2B spheroids, a range of prostate cancer cells (LNCaP, C4-2B, 22Rv1, PC-3), and prostate epithelial cells (PNT1). Extracellular FAs are the major source (∼83%) of carbons to the total lipid pool in all cell lines, compared with glucose (∼13%) and glutamine (∼4%), and FA oxidation rates are greater in prostate cancer cells compared with PNT1 cells, which preferentially partitioned extracellular FAs into triacylglycerols. Because of the higher rates of FA oxidation in C4-2B cells, cells remained viable when challenged by the addition of palmitate to culture media and inhibition of mitochondrial FA oxidation sensitized C4-2B cells to palmitate-induced apoptosis. Whereas in PC-3 cells, palmitate induced apoptosis, which was prevented by pretreatment of PC-3 cells with FAs, and this protective effect required DGAT-1–mediated triacylglycerol synthesis. These outcomes highlight for the first-time heterogeneity of lipid metabolism in prostate cancer cells and the potential influence that obesity-associated dyslipidemia or host circulating has on prostate cancer progression. Implications: Extracellular-derived FAs are primary building blocks for complex lipids and heterogeneity in FA metabolism exists in prostate cancer that can influence tumor cell behavior.

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Metadata

Authors
Balaban, S., Nassar, Z. D., Zhang, A. Y., Hosseini-Beheshti, E., Centenera, M. M., Schreuder, M., Lin, H.-M., Aishah, A., Varney, B., Liu-Fu, F., Lee, L. S., Nagarajan, S. R., Shearer, R. F., Hardie, R.-A., Raftopulos, N. L., Kakani, M. S., Saunders, D. N., Holst, J., Horvath, L. G., Butler, L. M., & Hoy, A. J.
Affiliations
  • 1Discipline of Physiology, School of Medical Sciences & Bosch Institute, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, New South Wales, Australia.
  • 2Adelaide Medical School and Freemasons Foundation Centre for Men's Health, University of Adelaide, Adelaide, South Australia, Australia.
  • 4Cancer Division, The Kinghorn Cancer Centre/Garvan Institute for Medical Research, Darlinghurst, New South Wales, Australia.
  • 5Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
  • 9School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
ORCID
Venue
Molecular Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2019-04-01
Volume
17
Issue
4
Pages
949-962
ISSN
  • 1541-7786
  • 1557-3125
DOI
10.1158/1541-7786.mcr-18-0347
Cited by
82
References
3
Language
en
Funders
  • Australian Research Council (FT130101004)
  • National Health and Medical Research Council (GNT1052963)

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