Manganese porphyrin, MnTE-2-PyP, treatment protects the prostate from radiation-induced fibrosis (RIF) by activating the NRF2 signaling pathway and enhancing SOD2 and sirtuin activity.,Free Radical Biology and Medicine

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Manganese porphyrin, MnTE-2-PyP, treatment protects the prostate from radiation-induced fibrosis (RIF) by activating the NRF2 signaling pathway and enhancing SOD2 and sirtuin activity.
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2020-03-25 , DOI: 10.1016/j.freeradbiomed.2020.03.014
Shashank Shrishrimal ₁ , Arpita Chatterjee ₁ , Elizabeth A Kosmacek ₁ , Paul J Davis ₂ , J Tyson McDonald ₃ , Rebecca E Oberley-Deegan ₁

Affiliation

Radiation therapy is a frequently used treatment for prostate cancer patients. Manganese (III) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP or T2E or BMX-010) and other similar manganese porphyrin compounds that scavenge superoxide molecules have been demonstrated to be effective radioprotectors and prevent the development of radiation-induced fibrosis (RIF). However, understanding the molecular pathway changes associated with these compounds remains limited for radioprotection. Recent RNA-sequencing data from our laboratory revealed that MnTE-2-PyP treatment activated the nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway. Therefore, we hypothesize that MnTE-2-PyP protects the prostate from RIF by activating the NRF2 signaling pathway. We identified that MnTE-2-PyP is a post-translational activator of NRF2 signaling in prostate fibroblast cells, which plays a major role in fibroblast activation and myofibroblast differentiation. The mechanism of NRF2 activation involves an increase in hydrogen peroxide and a corresponding decrease in kelch-like ECH-associated protein 1 (KEAP1) levels. Activation of NRF2 signaling leads to an increase in expression of NAD(P)H dehydrogenase [quinone] 1 (NQO1), nicotinamide adenine dinucleotide (NAD+) levels, sirtuin activity (nuclear and mitochondrial), and superoxide dismutase 2 (SOD2) expression/activity. Increase in mitochondrial sirtuin activity correlates with a decrease in SOD2 (K122) acetylation. This decrease in SOD2 K122 acetylation correlates with an increase in SOD2 activity and mitochondrial superoxide scavenging capacity. Further, in human primary prostate fibroblast cells, the NRF2 pathway plays a major role in the fibroblast to myofibroblast transformation, which is responsible for the fibrotic phenotype. In the context of radiation protection, MnTE-2-PyP fails to prevent fibroblast to myofibroblast transformation in the absence of NRF2 signaling. Collectively, our results indicate that the activation of the NRF2 signaling pathway by MnTE-2-PyP is at least a partial mechanism of radioprotection in prostate fibroblast cells.

中文翻译：

锰卟啉 (MnTE-2-PyP) 治疗可通过激活 NRF2 信号通路并增强 SOD2 和 Sirtuin 活性来保护前列腺免受辐射诱导纤维化 (RIF)。

放射治疗是前列腺癌患者常用的治疗方法。锰 (III) 内消旋四（N-乙基吡啶鎓-2-基）卟啉（MnTE-2-PyP 或 T2E 或 BMX-010）和其他类似的锰卟啉化合物可清除超氧化物分子，已被证明是有效的辐射防护剂并防止辐射诱导纤维化（RIF）的发展。然而，了解与这些化合物相关的分子途径变化对于辐射防护仍然有限。我们实验室最近的 RNA 测序数据显示，MnTE-2-PyP 治疗激活了核因子红细胞 2 相关因子 2 (NRF2) 信号通路。因此，我们假设 MnTE-2-PyP 通过激活 NRF2 信号通路来保护前列腺免受 RIF 侵害。我们发现 MnTE-2-PyP 是前列腺成纤维细胞中 NRF2 信号传导的翻译后激活剂，在成纤维细胞活化和肌成纤维细胞分化中发挥重要作用。NRF2 激活的机制涉及过氧化氢的增加和 kelch 样 ECH 相关蛋白 1 (KEAP1) 水平的相应降低。NRF2 信号传导的激活导致 NAD(P)H 脱氢酶 [醌] 1 (NQO1) 表达增加、烟酰胺腺嘌呤二核苷酸 (NAD+) 水平、sirtuin 活性（核和线粒体）和超氧化物歧化酶 2 (SOD2) 表达增加/活动。线粒体 Sirtuin 活性的增加与 SOD2 (K122) 乙酰化的减少相关。SOD2 K122 乙酰化的降低与 SOD2 活性和线粒体超氧化物清除能力的增加相关。此外，在人原代前列腺成纤维细胞中，NRF2 通路在成纤维细胞向肌成纤维细胞的转化中发挥着重要作用，这也是纤维化表型的原因。在辐射防护方面，在缺乏 NRF2 信号传导的情况下，MnTE-2-PyP 无法阻止成纤维细胞向肌成纤维细胞的转化。总的来说，我们的结果表明，MnTE-2-PyP 激活 NRF2 信号通路至少是前列腺成纤维细胞辐射保护的部分机制。

更新日期：2020-03-26

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