Orme, J. | Search bioRxiv

bioRxiv2026

Suppression of early pro-inflammatory senescent signature post-radiotherapy mitigates chronic bone damage

Cellular senescence has been implicated in the pathophysiology of radiotherapy-related bone loss. Based on our previous work, clearance of senescent cells using genetic and pharmacological tools alleviates the anomalies associated with radiation-associated bone deterioration. The pro-inflammatory senescence associated secretome referred to as senescence associated secretory phenotype (SASP), is a hallmark of cellular senescence. The modulation of SASP by senomorphic drugs, potentially can suppress the pro-inflammatory secretome of senescent cells, irrespective of the underlying senescence mechanism. In this study we tested a senomorphic drug, ruxolitinib, a Janus kinase inhibitor (JAKi), during acute and chronic radiotherapy related effects on the bone. Our clinical data indicate an early increase in several pro-inflammatory SASP proteins following radiotherapy of spinal metastasis in prostate cancer patients. Longitudinal assessment of SASP-related genes confirmed this acute elevation in several SASP markers in systemic circulation following irradiation of mouse femurs. In a proof-of-concept study, following two preclinical radiotherapy regimens of cumulative doses of 30Gy (5 x 6Gy) and 60Gy (5 x 12Gy), a senomorphic approach of JAKi treatment was more effective in alleviating radiation-related bone loss compared to the senolytic cocktail of D+Q. Early and intermittent suppression of SASP using JAK inhibitors alleviated chronic bone deterioration, diminished telomere dysfunction, lowered senescence and SASP marker expression, reduced bone-marrow adiposity, and mitigated radiation related lymphatic impairment. Overall, our study shows that early targeting of SASP proteins could be a potential therapeutic to prevent radiotherapy-related chronic bone loss and risk of fractures. Lay SummaryRadiotherapy as part of cancer treatment is correlated with an acute increase in senescent cells. Here we show that the pro-inflammatory senescence associated secretory phenotype (SASP) becomes much more prominent soon after radiotherapy in both patients and mice. Suppression of the SASP using a Janus kinase inhibitor, ruxolitinib, reduced the overall senescent cell burden, improved bone architecture by promoting bone formation, reduced bone marrow adiposity, and mitigated radiation-induced lymphatic impairment. Overall, these findings suggest that early inhibition of the SASP may help mitigate several bone anomalies and prevent long-term bone loss and fractures after radiotherapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/708630v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1487404org.highwire.dtl.DTLVardef@1b8e481org.highwire.dtl.DTLVardef@1a20032org.highwire.dtl.DTLVardef@baf75b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Selective inhibition of protein secretion by abrogating receptor-coat interactions during ER export.

Protein secretion is an essential cellular process that permits cell growth, movement and communication. Traffic of proteins within the eukaryotic secretory pathway is mediated by transport intermediates that bud from one compartment, populated with appropriate cargo proteins, and fuse with a downstream compartment to deliver their contents. Here, we explore the possibility that protein secretion can be selectively inhibited by perturbing protein-protein interactions that drive capture into transport vesicles. Human PCSK9 is a major determinant of cholesterol metabolism, whose secretion is mediated by a specific cargo adaptor of the ER export machinery, SEC24A. We map a series of protein-protein interactions between PCSK9, its ER export receptor, SURF4, and SEC24A, that mediate secretion of PCSK9. We show that the interaction between SURF4 and SEC24A can be inhibited by 4-PBA, a small molecule that occludes a cargo-binding domain of SEC24. This inhibition reduces secretion of PCSK9 and additional SURF4 clients that we identify by mass spectrometry, leaving other secreted cargoes unaffected. We propose that selective small molecule inhibition of cargo recognition by SEC24 is a potential therapeutic intervention for atherosclerosis and other diseases that are modulated by secreted proteins.

cell biology↗