Abstract
The re-proliferation of quiescent cancer cells is considered to be the primary contributor to prostate cancer (Pca) recurrence and progression. In this study, we investigated the inhibitory effect of safranal, a monoterpene aldehyde isolated from Crocus sativus (saffron), on the re-proliferation of quiescent Pca cells in vitro and in vivo. The results showed that safranal efficiently blocked the re-activation of quiescent Pca cells by downregulating the G0/G1 cell cycle regulatory proteins CDK2, CDK4, CDK6, and phospho-Rb at Ser807/811 and elevating the levels of cyclin-dependent kinase inhibitors, p21 and p27. Further investigation on the underlying mechanisms revealed that safranal suppressed the mRNA and protein expression levels of Skp2, possibly through the deregulation of the transcriptional activity of two major transcriptional factors, E2F1 and NF-κB subunits. Moreover, safranal inhibited AKT phosphorylation at Ser473 and deregulated both canonical and non-canonical NF-κB signaling pathways. Safranal suppressed the tumor growth of quiescent Pca cell xenografts in vivo. Furthermore, safranal-treated tumor tissues exhibited a reduction in Skp2, E2F1, NF-κB p65, p-IκBα (Ser32), c-MYC, p-Rb (Ser807), CDK4, CDK6, and CDK2 and an elevation of p27 and p21 protein levels. Therefore, our findings demonstrate that safranal suppresses cell cycle re-entry of quiescent Pca cells in vitro and in vivo plausibly by repressing the transcriptional activity of two major transcriptional activators of Skp2, namely, E2F1 and NF-κB, through the downregulation of AKT phosphorylation and NF-κB signaling pathways, respectively.
Highlights
Tumor heterogeneity stems from the complex process of growth and diversity of cells such as quiescent cancer cells (QCCs), a subpopulation that transiently retreats from the cell cycle and arrests in the G0 phase (Yeh and Ramaswamy, 2015)
Mounting evidence indicates that inhibiting retinoblastoma protein (Rb)-E2F1 signaling deregulates G0/G1-related cyclins, which eventually block QCCs from re-entering the cell cycle (Zetterberg et al, 1995; Yao et al, 2015; Xi et al, 2016; So and Cheung, 2018; Pennycook and Barr, 2020). c-MYC is a crucial regulator in cell cycle re-entry through the histone chaperone Facilitates Chromatin Transcription (Bi et al, 2019, 2020) and its E3 ligase FBXW7 (Xi et al, 2016)
To examine the inhibitory effect of safranal (Figure 1A) on cell cycle re-entry, quiescent LNCaP cells were re-activated by serum replenishment, while quiescent PC-3 cells were reseeded at low confluency, in addition to the indicated concentrations of safranal
Summary
Tumor heterogeneity stems from the complex process of growth and diversity of cells such as quiescent cancer cells (QCCs), a subpopulation that transiently retreats from the cell cycle and arrests in the G0 phase (Yeh and Ramaswamy, 2015). QCCs have been clinically garnering attention as they can re-enter the cell cycle, resulting in cancer progression, recurrence, metastasis, and treatment resistance (Krall et al, 2018; Luskin et al, 2018; Recasens and Munoz, 2019). Prostate cancer (Pca) recurrence following primary treatment remains a leading clinical challenge, occurring in up to 50% of patients after 10 years of postradical prostatectomy or radiotherapy (Hull et al, 2002). Consistent with the proposed treatment strategy for Pca recurrence, current research focuses on the mechanism of inhibiting the shift from a quiescent to a proliferative state. A few effective leading compounds have impeded the transition from a quiescent to a proliferative state (Xi et al, 2016; Bi et al, 2020), emphasizing the necessity to mine for potential therapeutic options, which could block QCCs’ re-entry and hinder cancer recurrence
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