PO.ET08.01 · 实验与分子治疗
线粒体丝氨酸/苏氨酸磷酸酶磷酸甘油酸变位酶5（PGAM5）是促进腹部放疗的新型靶点
Mitochondrial serine/threonine phosphatase, phosphoglycerate mutase 5 (PGAM5) is a novel target to promote abdominal radiotherapy
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摘要 Abstract
中文摘要
胰腺癌患者常接受放疗，这带来对小肠和胃肠道组织毒性的重大风险。胰腺癌的治疗结局往往取决于给予更高的放射剂量，因此，在不影响肿瘤放射敏感性的情况下最大限度减少胃肠道毒性的策略将使患者获益匪浅。放射诱导的氧化应激在肠上皮细胞的放射诱导毒性中发挥重要作用。然而，减轻胃肠道毒性需要通过激活WNT/beta-catenin信号来减少氧化应激并刺激上皮再生。线粒体丝氨酸/苏氨酸磷酸酶磷酸甘油酸变位酶5（PGAM5）参与氧化应激的激活以及WNT/beta-catenin信号的抑制。位于线粒体膜上的PGAM5抑制NRF2的核转位，从而抑制NRF2依赖的抗氧化基因表达。此外，PGAM5通过使DVL2（一种beta-catenin降解复合物）去磷酸化来诱导beta-catenin降解。我们观察到PGAM5表达在肠上皮中因照射而显著升高。在照射后24小时使用一种新型小分子调节剂LFHP-1c（3 mg/kg体重，皮下注射）对PGAM5进行药理学抑制，可减轻胃肠道毒性。接受2.5%骨髓屏蔽的部分身体照射（PBI）（LD100/15）后再给予LFHP-1c治疗的小鼠，其存活率显著改善（90%的小鼠存活超过30天）（p < 0.00002），而在照射对照组中所有小鼠均在14天内死亡。组织病理学分析表明，与未治疗的照射小鼠相比，LFHP-1c治疗小鼠的空肠切片中隐窝-绒毛结构得以保存。LFHP-1c治疗显著（p < 0.005）诱导NRF2的稳定和核转位，同时增加beta-catenin的核定位，表明照射肠上皮中WNT/beta-catenin信号通路被激活。在来自Lgr5/eGFP-IRES-Cre-ERT2; R26-ACTB-tdTomato-EGFP小鼠肠道的照射类器官中，LFHP-1c治疗显示出对放射诱导毒性的减轻以及Lgr5+肠道干细胞存活的显著改善。在胰腺肿瘤小鼠模型中，LFHP-1c治疗未影响Kras阳性KPC细胞的放射敏感性。总之，我们使用放射诱导基因毒性应激的小鼠模型和离体类器官模型进行的研究表明，PGAM5可作为提高腹部放疗治疗比的潜在靶点。
查看英文原文 English abstract
Pancreatic cancer patients frequently undergo radiotherapy, which carries a significant risk of toxicity to the small bowel and gastrointestinal tissues. Therapeutic outcomes in pancreatic cancer often depend on delivering higher radiation doses, and thus strategies that minimize gastrointestinal toxicity without compromising tumor radiosensitivity would be profoundly beneficial to patients. Radiation induced oxidative stress plays a significant role in radiation induced toxicity in intestinal epithelial cells. However, mitigation of gastrointestinal toxicity requires reduction of oxidative stress and stimulation of epithelial regeneration through activation of WNT/beta-catenin signaling. Mitochondrial serine/threonine phosphatase, phosphoglycerate mutase 5 (PGAM5), is involved in activation of oxidative stress along with inhibition of WNT/beta-catenin signaling. PGAM5, located in the mitochondrial membrane, inhibits nuclear translocation of NRF2 and thereby represses NRF2-dependent antioxidant gene expression. Moreover, PGAM5 induces beta-catenin degradation by dephosphorylating DVL2, a beta-catenin destruction complex . We have observed PGAM5 expression significantly increased in intestinal epithelium in response to irradiation. Pharmacological inhibition of PGAM5 using a novel small molecule-based modulator LFHP-1c (3 mg/kg BW, subcutaneous) at 24 hours post irradiation mitigates gastrointestinal toxicity. Mice exposed to partial body irradiation (PBI) with 2.5% bone marrow shielding (LD100/15) followed by LFHP-1c treatment demonstrated significant improvement of mice survival (90% mice survived beyond 30 day) (p< 0.00002) compared to irradiated control where all the mice died within 14 days. Histopathological analyses demonstrated preservation of crypt-villus structures in the jejunum sections of LFHP-1c-treated mice compared to untreated irradiated mice. LFHP-1c treatment significantly (p<0.005) induced stabilization and nuclear translocation of NRF2, along with increased nuclear localization of beta-catenin, indicating activation of the WNT/beta-catenin signaling pathway in the irradiated intestinal epithelium. LFHP-1c treatment in irradiated organoids from Lgr5/eGFP-IRES-Cre-ERT2; R26-ACTB-tdTomato-EGFP mice intestine demonstrated mitigation of radiation induced toxicity and significant improvement in Lgr5+ve intestinal stem cell survival. In mice model of Pancreatic tumors, LFHP-1c treatment did not compromise the radiosensitivity of Kras positive KPC cells. In conclusion, our studies using mice model of radiation induced genotoxic stress and ex vivo organoid model demonstrated that PGAM5 can be a potential target to promote therapeutic ratio for abdominal radiotherapy.
利益披露 Disclosure
S. H. Rehman, None..
R. Chugh, None..
P. Bhanja, None..
S. Krepel, None..
S. Saha, None.