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4 results on '"Meghna S. Kakani"'

1. Prostate cancer cell proliferation is influenced by LDL-cholesterol availability and cholesteryl ester turnover

Author

Nikki L. Raftopulos, Tinashe C. Washaya, Andreas Niederprüm, Antonia Egert, Mariam F. Hakeem-Sanni, Bianca Varney, Atqiya Aishah, Mariya L. Georgieva, Ellinor Olsson, Diandra Z. dos Santos, Zeyad D. Nassar, Blake J. Cochran, Shilpa R. Nagarajan, Meghna S. Kakani, Jordan F. Hastings, David R. Croucher, Kerry-Anne Rye, Lisa M. Butler, Thomas Grewal, and Andrew J. Hoy

Subjects
Prostate cancer, LDL, LDL-cholesterol, Cell proliferation, Cholesteryl ester, ACAT1, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Prostate cancer growth is driven by androgen receptor signaling, and advanced disease is initially treatable by depleting circulating androgens. However, prostate cancer cells inevitably adapt, resulting in disease relapse with incurable castrate-resistant prostate cancer. Androgen deprivation therapy has many side effects, including hypercholesterolemia, and more aggressive and castrate-resistant prostate cancers typically feature cellular accumulation of cholesterol stored in the form of cholesteryl esters. As cholesterol is a key substrate for de novo steroidogenesis in prostate cells, this study hypothesized that castrate-resistant/advanced prostate cancer cell growth is influenced by the availability of extracellular, low-density lipoprotein (LDL)-derived, cholesterol, which is coupled to intracellular cholesteryl ester homeostasis. Methods C4-2B and PC3 prostate cancer cells were cultured in media supplemented with fetal calf serum (FCS), charcoal-stripped FCS (CS-FCS), lipoprotein-deficient FCS (LPDS), or charcoal-stripped LPDS (CS-LPDS) and analyzed by a variety of biochemical techniques. Cell viability and proliferation were measured by MTT assay and Incucyte, respectively. Results Reducing lipoprotein availability led to a reduction in cholesteryl ester levels and cell growth in C4-2B and PC3 cells, with concomitant reductions in PI3K/mTOR and p38MAPK signaling. This reduced growth in LPDS-containing media was fully recovered by supplementation of exogenous low-density lipoprotein (LDL), but LDL only partially rescued growth of cells cultured with CS-LPDS. This growth pattern was not associated with changes in androgen receptor signaling but rather increased p38MAPK and MEK1/ERK/MSK1 activation. The ability of LDL supplementation to rescue cell growth required cholesterol esterification as well as cholesteryl ester hydrolysis activity. Further, growth of cells cultured in low androgen levels (CS-FCS) was suppressed when cholesteryl ester hydrolysis was inhibited. Conclusions Overall, these studies demonstrate that androgen-independent prostate cancer cell growth can be influenced by extracellular lipid levels and LDL-cholesterol availability and that uptake of extracellular cholesterol, through endocytosis of LDL-derived cholesterol and subsequent delivery and storage in the lipid droplet as cholesteryl esters, is required to support prostate cancer cell growth. This provides new insights into the relationship between extracellular cholesterol, intracellular cholesterol metabolism, and prostate cancer cell growth and the potential mechanisms linking hypercholesterolemia and more aggressive prostate cancer.

Published
2022
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2. Supplementary Figures 1-3 from Extracellular Fatty Acids Are the Major Contributor to Lipid Synthesis in Prostate Cancer

Author

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

Abstract

S1: Pretreatment of PC-3 and C4-2B cells with a FA Mix alters the response to palmitate lipotoxicity and serum-starvation. S2: Dose response assessment of palmitate supplementation on cell viability. S3: Pretreatment with the DGAT1 inhibitor AZD3988 does not affect PC-3 cell growth.

Published
2023
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3. Data from Extracellular Fatty Acids Are the Major Contributor to Lipid Synthesis in Prostate Cancer

Author

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

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.

Published
2023
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4. Extracellular Fatty Acids Are the Major Contributor to Lipid Synthesis in Prostate Cancer

Author

Zeyad D. Nassar, Meghna S. Kakani, Andrew J. Hoy, Hui-Ming Lin, Jeff Holst, Lisa S. Lee, Robert F. Shearer, Lisa G. Horvath, Darren N. Saunders, Elham Hosseini-Beheshti, Margaret M. Centenera, Lisa M. Butler, Seher Balaban, Shilpa R. Nagarajan, Mark Schreuder, Nikki L. Raftopulos, Frank Liu-Fu, Atqiya Aishah, Bianca Varney, Alison Yan Zhang, and Rae-Anne Hardie

Subjects
Male, 0301 basic medicine, Cancer Research, Palmitates, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Prostate, Cell Line, Tumor, LNCaP, medicine, Extracellular, Humans, Molecular Biology, Triglycerides, Chemistry, Fatty Acids, Prostatic Neoplasms, Extracellular Fluid, Lipid metabolism, Metabolism, Lipid Metabolism, medicine.disease, Lipids, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Oncology, Apoptosis, Cell culture, 030220 oncology & carcinogenesis, Cancer research
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.

Published
2019
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