Many tumours originate from cancer stem cells (CSCs), which is a small population of cells that display stem cell properties. However, the molecular mechanisms that regulate CSC frequency remain poorly understood. Here, using microarray screening in aldehyde dehydrogenase (ALDH)-positive CSC model, we identify a fundamental role for a lipid mediator sphingosine-1-phosphate (S1P) in CSC expansion. Stimulation with S1P enhances ALDH-positive CSCs via S1P receptor 3 (S1PR3) and subsequent Notch activation. CSCs overexpressing sphingosine kinase 1 (SphK1), an S1P-producing enzyme, show increased ability to develop tumours in nude mice, compared with parent cells or CSCs. Tumorigenicity of CSCs overexpressing SphK1 is inhibited by S1PR3 knockdown or S1PR3 antagonist. Breast cancer patient-derived mammospheres contain SphK1 þ /ALDH1 þ cells or S1PR3 þ /ALDH1 þ cells. Our findings provide new insights into the lipid-mediated regulation of CSCs via Notch signalling, and rationale for targeting S1PR3 in cancer.
Manipulation of protein stability with small molecules has a great potential for both basic research and clinical therapy. Recently, we have developed a series of hybrid small molecules named SNIPER (Specific and Non‐genetic IAP‐dependent Protein ERaser) that induces degradation of target proteins via ubiquitin‐proteasome system. Here we report the activities of SNIPER(ER) that targets estrogen receptor alpha (ERα) for degradation. SNIPER(ER) induced degradation of ERα and inhibited estrogen‐dependent expression of pS2 gene in an estrogen‐dependent breast cancer cell line MCF‐7. A proteasome inhibitor MG132 and siRNA‐mediated downregulation of cIAP1 abrogated the SNIPER(ER)‐induced ERα degradation, suggesting that the ERα is degraded by proteasome subsequent to cIAP1‐mediated ubiquitylation. Intriguingly, after the ERα degradation, the SNIPER(ER)‐treated MCF‐7 cells undergo rapid cell death. Detailed analysis indicated that SNIPER(ER) caused necrotic cell death accompanied by a release of HMGB1, a marker of necrosis, from the cells. Following the ERα degradation, reactive oxygen species (ROS) was produced in the SNIPER(ER)‐treated MCF‐7 cells, and an anti‐oxidant N‐acetylcysteine inhibited the necrotic cell death. These results indicate that SNIPER(ER) induces ERα degradation, ROS production and necrotic cell death, implying a therapeutic potential of SNIPER(ER) as a lead for the treatment of ERα‐positive breast cancers.
Photolabile 6-nitrobenzo[a]pyrene (6-nitroBaP) released nitric oxide (NO) under visible-light irradiation. The generation of NO and the concomitant formation of the 6-oxyBaP radical were confirmed by ESR. BaP quinones were also detected as further oxidized products of the 6-oxyBaP radical. No such photodegradation was observed with other nitrated BaPs, such as 1-nitroBaP and 3-nitroBaP. DNA-strand breakage, caused by photoexcited 6-nitroBaP, was closely related to its NO-releasing activity. MO calculations of nitrated BaP suggest that the perpendicular conformation of the nitro substituent to the aromatic ring is important for the release of NO with light. These findings may be useful for the development of a new type of NO donor.
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