Enantiomerically pure β-dipeptide derivative induces anticancer activity against human hormone-refractory prostate cancer through both PI3K/Akt-dependent and -independent pathways
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Mei-Ling Chan1, Chia-Chun Yu1, Jui-Ling Hsu1, Wohn-Jenn Leu1, She-Hung Chan1, Lih-Ching Hsu1, Shih-Ping Liu2,3, Polina M. Ivantcova4, Özdemir Dogan5, Stefan Bräse6,7, Konstantin V. Kudryavtsev4,8 and Jih-Hwa Guh1
1School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
2Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
3Department of Urology, National Taiwan University Hospital, Taipei, Taiwan
4Department of Medicinal Chemistry, Faculty of Chemistry, Lomonosov Moscow State University, Moscow, Russian Federation
5Department of Chemistry, Middle East Technical University, Ankara, Turkey
6Institute of Organic Chemistry, Karlsruhe Institute of Technology, Karlsruhe, Germany
7Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany
8Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow region, Russian Federation
Konstantin V. Kudryavtsev, email: [email protected]
Jih-Hwa Guh, email: [email protected]
Keywords: β-dipeptide, c-Myc, PI3K/Akt, mTOR, hormone-refractory prostate cancer
Received: October 21, 2016 Accepted: May 08, 2017 Published: May 20, 2017
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 IC50. 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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