5-<i>O</i>-(<i>N</i>-Boc-<span style="font-variant: small-caps">l</span>-Alanine)-Renieramycin T Induces Cancer Stem Cell Apoptosis via Targeting Akt Signaling

Abstract

Cancer stem cells (CSCs) drive aggressiveness and metastasis by utilizing stem cell-related signals. In this study, 5-O-(N-Boc-l-alanine)-renieramycin T (OBA-RT) was demonstrated to suppress CSC signals and induce apoptosis. OBA-RT exerted cytotoxic effects with a half-maximal inhibitory concentration of approximately 7 µM and mediated apoptosis as detected by annexin V/propidium iodide using flow cytometry and nuclear staining assays. Mechanistically, OBA-RT exerted dual roles, activating p53-dependent apoptosis and concomitantly suppressing CSC signals. A p53-dependent pathway was indicated by the induction of p53 and the depletion of anti-apoptotic Myeloid leukemia 1 (Mcl-1) and B-cell lymphoma 2 (Bcl-2) proteins. Cleaved poly (ADP-ribose) polymerase (Cleaved-PARP) was detected in OBA-RT-treated cells. Interestingly, OBA-RT exerted strong CSC-suppressing activity, reducing the ability to form tumor spheroids. In addition, OBA-RT could induce apoptosis in CSC-rich populations and tumor spheroid collapse. CSC markers, including prominin-1 (CD133), Octamer-binding transcription factor 4 (Oct4), and Nanog Homeobox (Nanog), were notably decreased after OBA-RT treatment. Upstream CSCs regulating active Akt and c-Myc were significantly decreased; indicating that Akt may be a potential target of action. Computational molecular modeling revealed a high-affinity interaction between OBA-RT and an Akt molecule. This study has revealed a novel CSC inhibitory effect of OBA-RT via Akt inhibition, which may improve cancer therapy.

Keywords

• l-alanine)-renieramycin T%22%2C%22default_operator%22%3A%22AND%22%7D%7D%7D"> 5-<i>O</i>-(<i>N</i>-Boc-<span style="font-variant: small-caps">l</span>-alanine)-renieramycin T
• <i>Xestospongia</i> sp.
• marine sponge
• lung cancer
• anti-cancer
• cancer stem cells