Enantiomerically pure β-dipeptide derivative induces anticancer activity against human hormone-refractory prostate cancer through both PI3K/Akt-dependent and -independent pathways
The use of peptides that target cancer cells and induce anticancer activities through various mechanisms is developing as a potential anticancer strategy. KUD983, an enantiomerically pure β-dipeptide derivative, displays potent activity against hormone-refractory prostate cancer (HRPC) PC-3 and DU14...
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Published in | Oncotarget Vol. 8; no. 57; pp. 96668 - 96683 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Impact Journals LLC
14.11.2017
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Subjects | |
Online Access | Get full text |
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Summary: | The use of peptides that target cancer cells and induce anticancer activities through various mechanisms is developing as a potential anticancer strategy. KUD983, an enantiomerically pure β-dipeptide derivative, displays potent activity against hormone-refractory prostate cancer (HRPC) PC-3 and DU145 cells with submicromolar IC
. KUD983 induced G1 arrest of the cell cycle and subsequent apoptosis associated with down-regulation of several related proteins including cyclin D1, cyclin E and Cdk4, and the de-phosphorylation of RB. The levels of nuclear and total c-Myc protein, which could increase the expression of both cyclin D1 and cyclin E, were profoundly inhibited by KUD983. Furthermore, it inhibited PI3K/Akt and mTOR/p70S6K/4E-BP1 pathways, the key signaling in multiple cellular functions. The transient transfection of constitutively active myristylated Akt (myr-Akt) cDNA significantly rescued KUD983-induced caspase activation but did not blunt the inhibition of mTOR/p70S6K/4E-BP1 signaling cascade suggesting the presence of both Akt-dependent and -independent pathways. Moreover, KUD983-induced effect was enhanced with the down-regulation of anti-apoptotic Bcl-2 members (e.g., Bcl-2, and Mcl-1) and IAP family members (e.g., survivin). Notably, KUD983 induced autophagic cell death using confocal microscopic examination, tracking the level of conversion of LC3-I to LC3-II and flow cytometric detection of acidic vesicular organelles-positive cells. In conclusion, the data suggest that KUD983 is an anticancer β-dipeptide against HRPCs through the inhibition of cell proliferation and induction of apoptotic and autophagic cell death. The suppression of signaling pathways regulated by c-Myc, PI3K/Akt and mTOR/p70S6K/4E-BP1 and the collaboration with down-regulation of Mcl-1 and survivin may explain KUD983-induced anti-HRPC mechanism. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1949-2553 1949-2553 |
DOI: | 10.18632/oncotarget.18040 |