Abstract
BackgroundThe widely recognized anti-cancer potential of aspirin has created a broad interest to explore the clinical benefits of aspirin in cancer therapy. However, the current understanding of the molecular mechanisms involved in the anti-cancer potential of aspirin remains limited.MethodsCancer stemness assays which contained ALDH, side population, chemo-resistance, sphere formation, and tumorigenesis were performed to validate aspirin function in vitro and in vivo. Histone modification assay was performed to check the effect of aspirin on histone methylation as well as the activity of HDAC and KDM6A/B. Inhibitor in vivo assay was performed to evaluate therapeutic effects of various inhibitor combination manners.ResultsIn regards to in vitro studies, aspirin diminishes cancer cell stemness properties which include reducing the ALDH+ subpopulation, side population, chemo-resistance, and sphere formation in three cancer types. In regards to in vivo studies, aspirin decreases tumor growth and metastasis and prolongs survival. In addition, our results showed that aspirin inhibits inflammation-related stemness gene expression (especially ICAM3) identified by a high-throughput siRNA platform. In regards to the underlying molecular mechanism of action, aspirin reduces histone demethylase (KDM6A/B) expression that mediates histone methylation and suppresses gene expression via a COX-independent manner. In regards to therapeutic strategies, aspirin combined HDM inhibitors, ICAM3 downstream signaling Src/PI3K inhibitors, or ICAM3 inhibitor Lifitigrast prevents cancer progression in vivo.ConclusionsThe aforementioned findings suggest a molecular model that explains how aspirin diminishes cancer cell stemness properties. These findings may provide novel targets for therapeutic strategies involving aspirin in the prevention of cancer progression.
Highlights
The widely recognized anti-cancer potential of aspirin has created a broad interest to explore the clinical benefits of aspirin in cancer therapy
In order to determine the effects of aspirin on cancer cell stemness, we investigated the Aspirin diminishes cancer cell metastasis and stemness properties in vivo In order to determine the effects of aspirin on cancer cell metastasis and stemness in vivo, we implanted 4T1luciferase cells into the fourth fat pad of female Balb/c mice
Our results showed that Intercellular adhesion molecule 3 (ICAM3), CCL16, Phosphodiesterase 3A (PDE3A), Proteinase 3 (PRTN3), SOX2, and OCT4 protein expression decreases in the aspirin-treated groups versus controls (Fig. 3b, Fig. S2A)
Summary
The widely recognized anti-cancer potential of aspirin has created a broad interest to explore the clinical benefits of aspirin in cancer therapy. Cancer stem cell (CSC) was found as the chief culprit to initiate tumor occurrence, to enhance tumor malignancy and to cause tumor recurrence, whereby the maintenance of cancer cell stemness mainly depends on the tumor micro-environment or called the “niche” [1,2,3]. The cancer cell stemness and the resultant tumor initiation/malignancy could be maintained by the tumor-associated inflammation factors within the tumor micro-environment (niche) [6, 7]. Our previous work presented a mediumthroughput siRNA screen platform to identify inflammation genes that regulate cancer cell stemness and obtained several novel candidates [8]. Agents that target these genes may inhibit both inflammation and cancer cell stemness at the same time
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