Macrocyclic peptides decrease c-Myc protein levels and reduce prostate cancer cell growth.
The oncoprotein c-Myc is often overexpressed in cancer cells, and the stability of this protein has major significance in deciding the fate of a cell. Thus, targeting c-Myc levels is an attractive approach for developing therapeutic agents for cancer treatment. In this study, we report the anti-cancer activity of the macrocyclic peptides [D-Trp]CJ-15,208 (cyclo[Phe-D-Pro-Phe-D-Trp]) and the natural product CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]). [D-Trp]CJ-15,208 reduced c-Myc protein levels in prostate cancer cells and decreased cell proliferation with IC50 values ranging from 2.0 to 16 µM in multiple PC cell lines. [D-Trp]CJ-15,208 induced early and late apoptosis in PC-3 cells following 48 hours treatment, and growth arrest in the G2 cell cycle phase following both 24 and 48 hours treatment. Down regulation of c-Myc in PC-3 cells resulted in loss of sensitivity to [D-Trp]CJ-15,208 treatment, while overexpression of c-Myc in HEK-293 cells imparted sensitivity of these cells to [D-Trp]CJ-15,208 treatment. This macrocyclic tetrapeptide also regulated PP2A by reducing the levels of its phosphorylated form which regulates the stability of cellular c-Myc protein. Thus [D-Trp]CJ-15,208 represents a new lead compound for the potential development of an effective treatment of prostate cancer.
['Mukhopadhyay|Archana|A|http://orcid.org/0000-0001-5929-9877', 'Hanold|Laura E|LE|', 'Thayele Purayil|Hamsa|H|', 'Gisemba|Solomon A|SA|', 'Senadheera|Sanjeewa N|SN|', 'Aldrich|Jane V|JV|http://orcid.org/0000-0002-7954-9850']
D017209:Apoptosis D049109:Cell Proliferation D015536:Down-Regulation D057809:HEK293 Cells D006801:Humans D008297:Male D010456:Peptides, Cyclic D010766:Phosphorylation D011467:Prostate D011471:Prostatic Neoplasms D016271:Proto-Oncogene Proteins c-myc D013237:Stereoisomerism D014364:Tryptophan
c-Myc Prostate cancer [D-Trp]CJ-15,208 CJ-15,208 apoptosis macrocyclic tetrapeptides cell cycle arrest