Cytostatic effect of the hypothalamic cytokine PRP-1 is mediated by mTOR and cMyc inhibition in high grade chondrosarcoma.
This study aimed to further elucidate the molecular mechanisms of antiproliferative action of proline rich polypeptide 1 (PRP-1) cytokine, produced by neurosecretory cells of the hypothalamus to be considered as alternative adjuvant therapy for metastatic chondrosarcoma, which does not respond to chemotherapy or radiation and currently without any effective treatment. Rapid cell proliferation assay of human primary cultures from high grade chondrosarcoma patients biopsies and human chondrosarcoma JJ012 cell line indicated 50 and 80% inhibition in PRP-1 treated samples correspondingly. Videomicroscopy detected that despite the treatment there are still dividing cells, meaning that cells are not in the state of dormancy, rather PRP-1 repressed the cell cycle progression, exhibited cytostatic effect. The mammalian target of rapamycin (mTOR) is an intracellular serine/threonine protein kinase that has a crucial role in a nutrient sensitive signaling pathway that regulates cell growth. Experiments with mTOR pathway after PRP-1 (10 μg/ml) treatment indicated statistically significant 30% inhibition of mTOR activity and its 56% inhibition in immunoprecipitates with PRP-1 concentrations effective for cell proliferation inhibition. Treatment with PRP- caused inhibition of mTOR and downstream target cMyc oncogenic transcription factor sufficient to trigger the cytostatic effect in high grade, but not in low grade chondrosarcomas. The fact that lower concentrations than 10 μg/ml peptide with cytostatic effect did not inhibit mTOR, but inhibited cMyc prompted us to assume that PRP-1 binds to two different receptors facilitating the antiproliferative effect.
Department of Orthopedics, UHealth, Miller School of Medicine, University of Miami, 1600 NW 10th Ave, Suite 8006 (r-2), Miami, FL 33136, USA. kgaloian@med.miami.edu
Karina
K
Galoian
Thomas H
TH
Temple
Armen
A
Galoyan
D023181:Antimicrobial Cationic Peptides; D045744:Cell Line, Tumor; D002813:Chondrosarcoma / Q000473:pathology*; D016207:Cytokines / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
D023181:Antimicrobial Cationic Peptides; D016207:Cytokines; C540268:PRP-1 peptide; D010455:Peptides; D016271:Proto-Oncogene Proteins c-myc; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
Oncogene. 2004 Apr 19;23(18):3217-21
15094771
Cancer Res. 1992 Mar 1;52(5):1107-13
1737370
J Clin Oncol. 2001 Jan 1;19(1):265-72
11134222
J Interferon Cytokine Res. 2001 Nov;21(11):951-9
11747627
Neurochem Res. 2005 Apr;30(4):507-25
16076021
J Immunol. 1990 Feb 15;144(4):1295-303
2137488
Neurochem Res. 2009 Dec;34(12):2117-21
19484491
Mol Cancer Ther. 2004 Oct;3(10):1301-10
15486197
J Clin Oncol. 2005 Dec 20;23(36):9369-76
16361637
Drug News Perspect. 2003 Jul-Aug;16(6):370-4
12973448
Curr Cancer Drug Targets. 2003 Jun;3(3):163-75
12769686
Curr Opin Cell Biol. 2006 Dec;18(6):598-608
17046224
Neurochem Res. 2006 Jun;31(6):795-803
16804761
Neurochem Res. 2009 Feb;34(2):379-85
18612811
Nature. 2005 Feb 3;433(7025):477-80
15690031
J Biol Chem. 2003 Feb 7;278(6):3656-63
12446670
Neurochem Res. 2002 Apr;27(4):305-12
11958532
Nature. 2010 Jun 3;465(7298):562-4
20520704
Neurochem Res. 2010 Jun;35(6):934-9
20087764
Neurochem Res. 2000 Oct;25(9-10):1343-55
11059805
Am J Clin Oncol. 1994 Jun;17(3):273-6
8192117
Neurochem Res. 2010 Apr;35(4):598-602
19949858
J Biol Chem. 1995 Sep 8;270(36):21176-80
7673150