Abstract
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.
Highlights
Carcinoma of the prostate is one of the most frequently diagnosed cancers in men
The phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a negative regulator of phosphoinositide 3-kinase (PI3K)/ Akt/mammalian target of rapamycin (mTOR) signaling, has been originally discovered as a tumor suppressor mutated and lost in various cancers [7] and the consequential increased PI3K activity is associated with a high Gleason score and with advanced pathological stage disease, suggesting a pivotal role of PI3K pathway in hormone-refractory prostate cancer (HRPC) [8, 9]
The analysis of fluorescence intensity and the population distribution showed that a high proportion of the lowernumbered generations retained the fluorescence after the exposure of PC-3 cells to both KUD983 (1 μM) and KUD984 (10 μM); the proliferation indices were significantly reduced by both compounds (Figure 1B)
Summary
Carcinoma of the prostate is one of the most frequently diagnosed cancers in men. With adequate treatment, the 5-year relative survival rate of localized and regional prostate cancers is 100% in the United States; the rate drops to less than 30% if a distant metastasis occurs at the time of diagnosis [1]. The growth of hormone-refractory prostate cancer (HRPC) occurs after an 18- to 24-month treatment [2]. The phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling pathway is always constitutively activated in advanced stages of prostate cancer [5, 6]. The phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a negative regulator of PI3K/ Akt/mTOR signaling, has been originally discovered as a tumor suppressor mutated and lost in various cancers [7] and the consequential increased PI3K activity is associated with a high Gleason score and with advanced pathological stage disease, suggesting a pivotal role of PI3K pathway in HRPC [8, 9]
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