Kumar Kamendra, Moon Bo-Hyun, Kumar Santosh, Angdisen Jerry, Kallakury Bhaskar V S, Fornace Albert J, Suman Shubhankar
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
Department of Pathology, Georgetown University Medical Center, Washington, DC 20057, USA.
Aging (Albany NY). 2025 Jan 8;17(1):97-115. doi: 10.18632/aging.206183.
Exposure to ionizing radiation (IR), both low-LET (e.g., X-rays, γ rays) and high-LET (e.g., heavy ions), increases the risk of gastrointestinal (GI) cancer. Previous studies have linked IR-induced GI cancer to cellular senescence associated secretory phenotype (SASP) signaling. This study explores the potential of senolytic therapy to mitigate IR-induced GI carcinogenesis. Male mice were exposed to γ and Si-ions (69 keV/μm) IR. Two months later, they were treated with the senolytic agent ABT-263 orally for 5 days/week until euthanasia, followed by tumor counting and biospecimen collection at five months post-exposure. Tumors were classified as adenoma or carcinoma by a pathologist. Serum cytokine levels were measured, and the markers of senescence (p16), SASP (IL6), and oncogenic β-catenin signaling were assessed using immunostaining of intestinal tissue. Both low- and high-LET radiation exposure led to an increased frequency of adenoma and carcinoma in mice, accompanied by increased cellular senescence, acquisition of SASP, and overexpression of BCL-XL protein in a subset of these cells. Furthermore, administration of ABT-263 resulted in the elimination of senescent/SASP cells, a decrease in pro-inflammatory cytokines (TNFRSF1B, CCL20, CXCL4, P-selectin, CCL27, and CXCL16) at the systemic level, and downregulation of β-catenin signaling that coincided with decreased GI cancer development. This study suggests a link between IR-induced senescent/SASP cell accumulation and GI cancer development. It also shows that the senolytic agent ABT-263 can regulate IR-induced inflammatory cytokines and carcinogenic mediators both systemically and in intestinal tissue. These findings support the potential of senolytic intervention to reduce IR-induced GI cancer risk.
暴露于低传能线密度（LET）（如X射线、γ射线）和高传能线密度（如重离子）的电离辐射（IR）会增加胃肠道（GI）癌的风险。先前的研究已将IR诱导的GI癌与细胞衰老相关分泌表型（SASP）信号联系起来。本研究探讨了衰老细胞溶解疗法减轻IR诱导的GI致癌作用的潜力。雄性小鼠暴露于γ射线和硅离子（69 keV/μm）IR。两个月后，每周5天口服衰老细胞溶解剂ABT-263直至安乐死，随后在暴露后五个月进行肿瘤计数和生物标本采集。病理学家将肿瘤分类为腺瘤或癌。测量血清细胞因子水平，并使用肠道组织免疫染色评估衰老标志物（p16）、SASP（IL6）和致癌β-连环蛋白信号。低传能线密度和高传能线密度辐射暴露均导致小鼠腺瘤和癌的发生率增加，同时细胞衰老增加、获得SASP以及这些细胞亚群中BCL-XL蛋白的过表达。此外，给予ABT-263可消除衰老/SASP细胞，在全身水平降低促炎细胞因子（TNFRSF1B、CCL20、CXCL4、P-选择素、CCL27和CXCL16），并下调β-连环蛋白信号，这与GI癌发展减少相一致。本研究表明IR诱导的衰老/SASP细胞积累与GI癌发展之间存在联系。它还表明衰老细胞溶解剂ABT-263可在全身和肠道组织中调节IR诱导的炎性细胞因子和致癌介质。这些发现支持衰老细胞溶解干预降低IR诱导的GI癌风险的潜力。
