Prostate cancer cell proliferation is influenced by LDL-cholesterol availability and cholesteryl ester turnover.
ACAT1
Cell proliferation
Cholesteryl ester
HSL
LDL
LDL-cholesterol
Prostate cancer
nCEH1
Journal
Cancer & metabolism
ISSN: 2049-3002
Titre abrégé: Cancer Metab
Pays: England
ID NLM: 101607582
Informations de publication
Date de publication:
15 Jan 2022
15 Jan 2022
Historique:
received:
16
09
2021
accepted:
24
11
2021
entrez:
16
1
2022
pubmed:
17
1
2022
medline:
17
1
2022
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
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.
Identifiants
pubmed: 35033184
doi: 10.1186/s40170-021-00278-1
pii: 10.1186/s40170-021-00278-1
pmc: PMC8760736
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1Subventions
Organisme : Movember Foundation
ID : MRTA3
Organisme : Movember Foundation
ID : MRTA3
Informations de copyright
© 2022. The Author(s).
Références
Nat Rev Urol. 2017 Feb;14(2):107-119
pubmed: 27779230
Cancer Discov. 2020 Dec;10(12):1797-1807
pubmed: 33139243
Elife. 2020 Jun 09;9:
pubmed: 32513387
Cancer Epidemiol Biomarkers Prev. 2009 Nov;18(11):2807-13
pubmed: 19887582
Cancer Res. 2008 Aug 1;68(15):6407-15
pubmed: 18676866
Cancer Discov. 2012 May;2(5):401-4
pubmed: 22588877
Int J Cancer. 2001 Jan 1;91(1):41-5
pubmed: 11149418
Vascul Pharmacol. 2014 Jan;60(1):42-8
pubmed: 24315856
Anticancer Res. 2019 Jul;39(7):3385-3394
pubmed: 31262860
Mol Carcinog. 2014 Oct;53(10):807-19
pubmed: 23661506
Cancer Res. 2019 Jul 1;79(13):3320-3331
pubmed: 31064850
Cell Rep. 2014 May 8;7(3):883-97
pubmed: 24746815
Biochim Biophys Acta. 2016 Sep;1861(9 Pt A):1066-1075
pubmed: 27320013
Prostate Cancer Prostatic Dis. 2021 Jul 29;:
pubmed: 34326474
Mol Cell Endocrinol. 2007 Feb;265-266:42-5
pubmed: 17208360
Cell Metab. 2014 Mar 4;19(3):393-406
pubmed: 24606897
Cancer Metab. 2021 Jan 7;9(1):2
pubmed: 33413672
Clin Cancer Res. 2018 Nov 1;24(21):5433-5444
pubmed: 30042207
Prostate Cancer Prostatic Dis. 2020 Sep;23(3):475-485
pubmed: 32029930
Cancer Metab. 2020 Jun 19;8:11
pubmed: 32577235
Cancer Res. 2012 Apr 1;72(7):1878-89
pubmed: 22350410
J Lipid Res. 2010 Oct;51(10):2896-908
pubmed: 20625037
BMC Med Genomics. 2010 Mar 16;3:8
pubmed: 20233430
Curr Opin Endocrinol Diabetes Obes. 2012 Apr;19(2):136-41
pubmed: 22262001
J Biol Chem. 1957 May;226(1):497-509
pubmed: 13428781
Biochim Biophys Acta. 1993 Apr 23;1167(3):316-25
pubmed: 8481394
Cancer Causes Control. 2008 Dec;19(10):1259-66
pubmed: 18704722
Eur Urol Oncol. 2019 Feb;2(1):28-36
pubmed: 30929843
PLoS One. 2012;7(1):e30062
pubmed: 22279565
Cancer Cell. 2011 May 17;19(5):575-86
pubmed: 21575859
Science. 2017 Mar 24;355(6331):1306-1311
pubmed: 28336668
Res Rep Urol. 2021 Jun 30;13:457-472
pubmed: 34235102
J Steroid Biochem Mol Biol. 2015 Jul;151:102-7
pubmed: 25218443
Cancer Res. 1999 Jan 15;59(2):279-84
pubmed: 9927031
Mol Endocrinol. 2012 May;26(5):833-45
pubmed: 22422617
Exp Biol Med (Maywood). 2019 Oct;244(13):1053-1061
pubmed: 31573840
BMC Cancer. 2012 Jan 19;12:25
pubmed: 22260413
J Cancer. 2021 May 19;12(14):4307-4321
pubmed: 34093831
Angiogenesis. 2013 Jul;16(3):625-37
pubmed: 23429999
Life Sci. 2019 Sep 1;232:116592
pubmed: 31228515
Contemp Oncol (Pozn). 2012;16(6):491-7
pubmed: 23788934
Int J Cancer. 2016 Sep 15;139(6):1281-8
pubmed: 27176735
Sci Signal. 2013 Apr 02;6(269):pl1
pubmed: 23550210
Pharm Res. 2011 Mar;28(3):423-37
pubmed: 20683646
Mediators Inflamm. 2019 Aug 22;2019:6163130
pubmed: 31534437
Urol Clin North Am. 2021 Aug;48(3):339-347
pubmed: 34210489
J Cell Physiol. 2021 Jul;236(7):5253-5264
pubmed: 33368314
Endocrinology. 2011 Jan;152(1):48-58
pubmed: 21106876
Cancer Metab. 2020 Nov 23;8(1):25
pubmed: 33292612
Cell Mol Life Sci. 2020 Jul;77(14):2839-2857
pubmed: 31664461
J Clin Oncol. 2017 Oct 10;35(29):3272-3274
pubmed: 28817369
PLoS One. 2010 Dec 03;5(12):e14175
pubmed: 21151972
Cancer Causes Control. 2010 Jan;21(1):61-8
pubmed: 19806465
World J Mens Health. 2016 Apr;34(1):28-33
pubmed: 27169126
Prostate. 2014 Apr;74(4):372-80
pubmed: 24311408
Mol Cell. 2019 Oct 17;76(2):220-231
pubmed: 31586545
Biochim Biophys Acta Mol Basis Dis. 2019 May 1;1865(5):879-894
pubmed: 29883718