Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Journal of Ovarian Research
Published in: Journal of Ovarian Research 1/2010

Open Access 01-12-2010 | Research

Anti-proliferative effect of LXR agonist T0901317 in ovarian carcinoma cells

Authors: James J Rough, M Alexandra Monroy, Smitha Yerrum, John M Daly

Published in: Journal of Ovarian Research | Issue 1/2010

Login to get access

Abstract

Background

Ovarian cancer is the most common cause of cancer related death from gynecologic tumors in the United States. The insidious nature of the disease precludes early diagnosis, therefore surgical debulking and chemotherapy are considered as standard treatment modalities for advanced stages. We investigated the effect of the LXR agonist, T0901317, on ovarian cancer cell proliferation and apoptosis as a potential therapeutic agent.

Results

T0901317 treatment resulted in a significant (P <0.001) inhibition of cell proliferation in a time- and dose-dependent manner in CaOV3, SKOV3 and A2780 cells. Western blot analysis demonstrated an induction of p21 and p27 with a concominant reduction in phospho-RB protein levels. Cell cycle analysis demonstrated a significant (P <0.001) arrest in the G1 cell cycle phase. Significant induction of Caspase-3 and BAX gene expression occurred with treatment. Induction of apoptosis was confirmed by significant (P < 0.001) elevation of caspase activity on FACS analysis, caspase-glo assay, BAX protein induction and decreased caspase 3 precursor protein expression on Western blot analysis. LXR α/β knockdown experiments did not reverse the anti-proliferative and cytotoxic effects of T0901317.

Conclusions

The LXR agonist, T0901317, significantly suppresses cell proliferation and induces programmed cell death in a dose- and time-dependent manner. Our results indicate that T0901317 induces its anti-proliferative and cytotoxic effects via an LXR-independent mechanism.
Appendix
Available only for authorised users
Literature
1.
Edwards BK, Howe HL, Ries LA, Thun MJ, Rosenberg HM, Yancik R, Wingo PA, Jemal A, Feigal EG: Annual report to the nation on the status of cancer, 1973–1999, featuring implications of age and aging on U.S. cancer burden. Cancer 2002, 94: 2766–92. 10.1002/cncr.10593CrossRefPubMed
2.
Jemal A, Siegel T, Ward E, Hao Y, Murray T, Thun MJ: Cancer statistics. CA Cancer J Clin 2008, 55: 10–30. 10.3322/canjclin.55.1.10CrossRef
3.
Goff BA, Mandel LS, Melancon CH, Muntz HG: Frequency of symptoms of ovarian cancer in women presenting to primary care clinics. JAMA 2004, 22: 2705–12. 10.1001/jama.291.22.2705CrossRef
4.
Burg ME, van Lent M, Buyse M: The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer: Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer. N Engl J Med 1995, 10: 629–34. 10.1056/NEJM199503093321002CrossRef
5.
Apfel R, Benbrook D, Lernhardt E, Ortiz MA, Salbert G, Pfahl M: A novel orphan receptor specific for a subset of thyroid hormone-responsive elements and its interaction with the retinoid/thyroid hormone receptor subfamily. Mol Cell Biol 1994, 14: 7025–35.PubMedCentralPubMed
6.
Lu TT, Repa JJ, Mangelsdorf DJ: Orphan nuclear receptors as eLiXiRs and FiXeRs of sterol metabolism. J Biol Chem 2001, 276: 37735–8.CrossRefPubMed
7.
Willy PJ, Umesono K, Ong ES, Evans RM, Heyman RA, Mangelsdorf DJ: LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev 1995, 9: 1033–45. 10.1101/gad.9.9.1033CrossRefPubMed
8.
Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA, Willson TM: Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 1997, 272: 3137–40. 10.1074/jbc.272.6.3137CrossRefPubMed
9.
Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ: Nuclear receptors and lipid physiology: opening the X-files. Science 2001, 294: 1866–70. 10.1126/science.294.5548.1866CrossRefPubMed
10.
Castrillo A, Tontonoz P: Nuclear receptors in macrophage biology: at the crossroads of lipid metabolism and inflammation. Annu Rev Cell Dev Biol 2004, 20: 455–80. 10.1146/annurev.cellbio.20.012103.134432CrossRefPubMed
11.
Chuu CP, Chen RY, Hiipakka RA, Kokontis JM, Warner KV, Xiang J, Liao S: The liver X receptor agonist T0901317 acts as androgen receptor antagonist in human prostate cancer cells. Biochem Biophys Res Commun 2007, 57: 341–6. 10.1016/j.bbrc.2007.03.116CrossRef
12.
Chuu CP, Hiipakka RA, Kokontis JM, Fukuchi J, Chen RY, Liao S: Inhibition of tumor growth and progression of LNCaP prostate cancer cells in athymic mice by androgen and liver X receptor agonist. Cancer Res 2006, 66: 6482–6. 10.1158/0008-5472.CAN-06-0632CrossRefPubMed
13.
Fukuchi J, Kokontis JM, Hiipakka RA, Chuu CP, Liao S: Antiproliferative effect of liver X receptor agonists on LNCaP human prostate cancer cells. Cancer Res 2004, 64: 7686–9. 10.1158/0008-5472.CAN-04-2332CrossRefPubMed
14.
Vigushin DM, Dong Y, Inman L, Peyvandi N, Alao JP, Sun C, Ali S, Niesor EJ, Bentzen CL, Coombes RC: The nuclear oxysterol receptor LXRalpha is expressed in the normal human breast and in breast cancer. Med Oncol 2004, 21: 123–31. 10.1385/MO:21:2:123CrossRefPubMed
15.
Wente W, Brenner MB, Zitzer H, Gromada J, Efanov AM: Activation of liver X receptors and retinoid X receptors induces growth arrest and apoptosis in insulin-secreting cells. Endocrinology 2007, 148: 1843–9. 10.1210/en.2006-1247CrossRefPubMed
16.
Pfisterer J, Plante M, Vergote I, du Bois A, Hirte H, Lacave AJ: Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Onco 2006, 29: 4699–707. 10.1200/JCO.2006.06.0913CrossRef
17.
18.
Birrell M, Catley M, Hardaker E, Wong S, Willson T, McCluskie K, Leonard T, Farrow S, Collins J, Haj-Yahai S, Belvisi M: Novel Role for the liver X nuclear receptor in suppression of lung inflammatory responses. J Biol Chem 2007, 44: 31822–90.
19.
Mitro N, Vargas L, Romeo R, Koder A, Saez E: T0901317 is a potent PXR ligand: Implications for the biology ascribed to LXR. FEBS Letters 2007, 9: 1721–1726. 10.1016/j.febslet.2007.03.047CrossRef
20.
Houck KA, Borchert KM, Hepler CD, Thomas JS, Bramlett KS, Michael LF, Burris TP: T0901317 is a dual LXR/FXR agonist. Molecular Genetics and Metabolism 2004, 83: 184–187. 10.1016/j.ymgme.2004.07.007CrossRefPubMed
21.
Alberts DS, Hallum AV III, Stratton-Custis M, Garcia DJ, Gleason-Guzman M, Salmon SE, Santabarbara P, Niesor EJ, Floret S, Bentzen CL: Phase I Pharmacokinetic Trial and Correlative in Vitro Phase II Tumor Kinetic Study of Apomine (SR-45023 A), a Novel Oral Biphosphonate Anticancer Drug. Clinical Cancer Research 2001, 7: 1246–1250.PubMed
22.
Swales KE, Korbonits M, Carpenter R, Walsh DT, Warner TD, Bishop-Bailey D: The Farsenoid X Receptor Is Expressed in Breast Cancer and Regulates Apoptosis and Aromatase Expression. Cancer Research 2006, 20: 10120–10126. 10.1158/0008-5472.CAN-06-2399CrossRef
23.
Choonjans K, Auwerx J: A Sharper Image of SHP. Nature 2002, 8: 789–791. 10.1038/nm0802-789
24.
Sherr CJ, Roberts JM: CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999, 13: 1501–12. 10.1101/gad.13.12.1501CrossRefPubMed
25.
Connell-Crowley L, Harper JW, Goodrich DW: Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation. Mol Biol Cell 1997, 8: 287–301.PubMedCentralCrossRefPubMed
26.
Gayathri R, Gunadharini DN, Arunkumar A, Senthilkumar K, Krishnamoorthy G, Banudevi S, Vignesh RC, Arunakaran J: Effects of diallyl disulfide (DADS) on expression of apoptosis associated proteins in androgen independent human prostate cancer cells (PC-3). Mol Cell Biochem 2009, 320: 197–203. 10.1007/s11010-008-9903-5CrossRefPubMed
Metadata
Title
Anti-proliferative effect of LXR agonist T0901317 in ovarian carcinoma cells
Authors
James J Rough
M Alexandra Monroy
Smitha Yerrum
John M Daly
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Journal of Ovarian Research / Issue 1/2010
Electronic ISSN: 1757-2215
DOI
https://doi.org/10.1186/1757-2215-3-13

Other articles of this Issue 1/2010

Journal of Ovarian Research 1/2010 Go to the issue

Research

Radiolabeling, biodistribution and gamma scintigraphy of noscapine hydrochloride in normal and polycystic ovary induced rats

Research

Identification and characterization of a spontaneous ovarian carcinoma in Lewis rats

Research

Mural granulosa cell gene expression associated with oocyte developmental competence

Research

Increased androgen receptor expression in serous carcinoma of the ovary is associated with an improved survival

Brief communication

Endometriosis-associated ovarian cancer: A ten-year cohort study of women living in the Estrie Region of Quebec, Canada

Review

The detection, treatment, and biology of epithelial ovarian cancer