Molecular mechanisms of translational control in sunitinib-induced vascular dysfunction

PROJECT SUMMARY The vasculature is lined by endothelial cells (ECs). Emerging studies have revealed remarkable endothelial heterogeneity across distinct tissues, in part dictated by environmental signals from the tissue microenvironment. EC homeostasis is also tightly controlled by various transcription factors leading to cell-autonomous changes in gene expression. Although the field of transcriptome analysis has greatly expanded our understanding of endothelial biology, the extent to which mRNA translational control contributes to the dynamic regulation of ECs, especially under stress, remains less characterized. Translational control is a key regulatory mechanism that controls protein abundance and thereby dictates identity and functions across cell types and tissues. In the present study, we sought to investigate the molecular mechanisms by which sunitinib, a tyrosine kinase inhibitor (TKI), induces endothelial dysfunction. Sunitinib, a multireceptor TKI, is used as the first-line therapy for solid tumors such as metastatic renal cell carcinoma. Despite its effectiveness, a considerable number of patients receiving sunitinib suffer from cardiac and vascular toxic effects. While mechanisms of cardiomyocyte toxicity have been identified, much less is known about the effects of sunitinib on vascular dysfunction. Thus, a better understanding of sunitinib-induced vascular toxicity and its underlying mechanisms is critical to mitigate its risk. As a convergent mechanism downstream of most oncogenic signals, translational rewiring is known to play a key role in promoting cancer onset and progression. Whether such a regulatory program functions in the context of cardio-oncology remains largely unknown. Our preliminary data suggest that translation is dysregulated in sunitinib-treated ECs, leading to translational inhibition of SND1 (Staphylococcal nuclease domain-containing protein 1), a gene with unknown function in ECs. We established SND1 as a potential novel regulator of endothelial health, in part due to its cooperation with UBE2N in regulating the DNA damage response signaling pathway upon sunitinib exposure. Using in silico repurposing of FDA-approved drugs followed by in vitro testing, ramipril, an angiotensin-converting enzyme inhibitor, mitigates sunitinib-induced vascular damage. Therefore, in Aim 1 of the proposed studies, our goal is to define the molecular roadmap by which sunitinib translationally regulates SND1. In Aim 2 of the proposed studies, we aim to dissect the role of SND1 as an important mediator of endothelial tolerance against sunitinib through its interplay with UBE2N in regulating DNA damage repair. In Aim 3, we will validate the cardioprotective effects of ramipril in vivo and confirm that it will not interfere with the effectiveness of sunitinib against tumor growth. Completion of the proposed studies will produce critical insights into the role of translational control in sunitinib-induced vascular dysfunction and will fundamentally advance our understanding of the interaction between translation and endothelial homeostasis in general.