Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China.
Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, P.R. China.
Cell Death Dis. 2021 Mar 12;12(3):265. doi: 10.1038/s41419-021-03557-3.
NOXA, a BH3-only proapoptotic protein involved in regulating cell death decisions, is highly expressed but short-lived in colorectal cancer (CRC). Neddylated cullin-5 (CUL5)-mediated ubiquitination and degradation of NOXA is crucial to prevent its overaccumulation and maintain an appropriate action time. However, how this process is manipulated by CRC cells commonly exposed to oxidative stress remain unknown. The peroxiredoxin PRDX1, a conceivable antioxidant overexpressed in CRC tissues, has been shown to inhibit apoptosis and TRAF6 ubiquitin-ligase activity. In this study, we found that PRDX1 inhibits CRC cell apoptosis by downregulating NOXA. Mechanistically, PRDX1 promotes NOXA ubiquitination and degradation, which completely depend on CUL5 neddylation. Further studies have demonstrated that PRDX1 oligomers bind with both the Nedd8-conjugating enzyme UBE2F and CUL5 and that this tricomplex is critical for CUL5 neddylation, since silencing PRDX1 or inhibiting PRDX1 oligomerization greatly dampens CUL5 neddylation and NOXA degradation. An increase in reactive oxygen species (ROS) is not only a hallmark of cancer cells but also the leading driving force for PRDX1 oligomerization. As shown in our study, although ROS play a role in upregulating NOXA mRNA transcription, ROS scavenging in CRC cells by N-acetyl-L-cysteine (NAC) can significantly reduce CUL5 neddylation and extend the NOXA protein half-life. Therefore, in CRC, PRDX1 plays a key role in maintaining intracellular homeostasis under conditions of high metabolic activity by reinforcing UBE2F-CUL5-mediated degradation of NOXA, which is also evidenced in the resistance of CRC cells to etoposide treatment. Based on these findings, targeting PRDX1 could be an effective strategy to overcome the resistance of CRC to DNA damage-inducing chemotherapeutics.
NOXA 是一种 BH3 结构域仅包含的促凋亡蛋白，参与调控细胞死亡决策，在结直肠癌（CRC）中高度表达但半衰期短。Neddylated 环化酶 5（CUL5）介导的 NOXA 泛素化和降解对于防止其过度积累和维持适当的作用时间至关重要。然而，CRC 细胞通常暴露于氧化应激下，该过程如何被操纵仍不清楚。过氧化物还原酶 PRDX1 是 CRC 组织中过表达的一种可想象的抗氧化剂，已被证明可以抑制细胞凋亡和 TRAF6 泛素连接酶活性。在这项研究中，我们发现 PRDX1 通过下调 NOXA 抑制 CRC 细胞凋亡。从机制上讲，PRDX1 促进了 NOXA 的泛素化和降解，这完全依赖于 CUL5 的 Neddylation。进一步的研究表明，PRDX1 寡聚体与 Nedd8 连接酶 UBE2F 和 CUL5 结合，并且该三聚体对于 CUL5 的 Neddylation 至关重要，因为沉默 PRDX1 或抑制 PRDX1 寡聚化会大大抑制 CUL5 的 Neddylation 和 NOXA 的降解。活性氧（ROS）的增加不仅是癌细胞的一个标志，也是 PRDX1 寡聚化的主要驱动力。如我们的研究所示，尽管 ROS 在上调 NOXA mRNA 转录中起作用，但 CRC 细胞中 ROS 通过 N-乙酰-L-半胱氨酸（NAC）的清除可以显著降低 CUL5 的 Neddylation 并延长 NOXA 蛋白半衰期。因此，在 CRC 中，PRDX1 通过加强 UBE2F-CUL5 介导的 NOXA 降解，在高代谢活性条件下维持细胞内稳态中发挥关键作用，这也在 CRC 细胞对依托泊苷治疗的耐药性中得到证实。基于这些发现，针对 PRDX1 可能是克服 CRC 对诱导 DNA 损伤的化学疗法耐药性的有效策略。
