Enantiomerically pure β-dipeptide derivative induces anticancer activity against human hormone-refractory prostate cancer through both PI3K/Akt-dependent and -independent pathwaysстатья
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Аннотация: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.