Abstract
Activation of acid sphingomyelinase (SMPD1) and the generation of ceramide is a critical regulator of apoptosis in response to cellular stress including radiation. Endothelial SMPD1 has been shown to regulate tumor responses to radiation therapy. We show here that the SMPD1 gene is regulated by a microRNA (miR), miR-15a, in endothelial cells (ECs). Standard low dose radiation (2 Gy) upregulates miR-15a and decreases SMPD1 levels. In contrast, high dose radiation (10 Gy and above) decreases miR-15a and increases SMPD1. Ectopic expression of miR-15a decreases both mRNA and protein levels of SMPD1. Mimicking the effects of high dose radiation with a miR-15a inhibitor decreases cell proliferation and increases active Caspase-3 & 7. Mechanistically, inhibition of miR-15a increases inflammatory cytokines, activates caspase-1 inflammasome and increases Gasdermin D, an effector of pyroptosis. Importantly, both systemic and vascular-targeted delivery of miR-15a inhibitor decreases angiogenesis and tumor growth in a CT26 murine colorectal carcinoma model. Taken together, our findings highlight a novel role for miR mediated regulation of SMPD1 during radiation responses and establish proof-of-concept that this pathway can be targeted with a miR inhibitor.
Highlights
Technological advances such as stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS)[1,2,3,4,5] have allowed significant improvements in therapeutic radiation dose escalation
Our studies show that miR-15a targets SMPD1 in endothelial cells (ECs) and inhibition of miR-15a decreases EC and tumor cell proliferation, enhances cell death and diminishes tumor growth in a mouse CT26 colorectal carcinoma flank tumor model
We first evaluated the expression of SMPD1 in human cancers and asked if the levels of SMPD1 correlated with overall survival (Fig. 1) using the online database KMplotter
Summary
Technological advances such as stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS)[1,2,3,4,5] have allowed significant improvements in therapeutic radiation dose escalation. IR-mediated cell death combined with a pro-inflammatory state contributes to an immunostimulatory profile leading to further immunogenic cell death (ICD)[15,16] In this context, we hypothesized that transcriptional programs in the endothelia triggered by different radiation doses dictated the overall tumor response to radiation. Our findings establish a new miR based regulatory pathway that affects SMPD1 and vascular cell death in response to radiation dose. Inhibition of this pathway may mimic features of high dose radiation and offers avenues for the development of targeted therapeutics
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
