Cullin-5 neddylation-mediated NOXA degradation is enhanced by PRDX1 oligomers in colorectal cancer

Abstract

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.

Disruption of Colorectal Cancer Network by Polyphyllins Reveals Pivotal Entities with Implications for Chemoimmunotherapy

“…Moreover, targeting peroxiredoxin-1 is considered as one of the novel strategies for treatment of colorectal cancers [32]. Recently it has been reported that, to overcome resistance to DNA-damaging agents like etoposide, targeting peroxiredoxin-1 could be a beneficial strategy [33]. As observed in the present study, action of Polyphyllins PD and PII in downregulating the key molecule peroxiredoxin-1 could be employed to achieve this novel treatment option.…”

A Comprehensive Review of Biological Roles and Interactions of Cullin-5 Protein

“…The activation of mitochondrial and intrinsic pathways by NOXA is critical for the survival of cancer cells. Xu and his team have shown that the neddylation and ubiquitination complexes of UBE2F–Cul5–RBX2 and UBE2M–Parkin/DJ-1 enzymes regulate apoptosis from NOXA turnover . First, UBE2F, one of two neddylators of the ubiquitin-conjugated enzyme (E2), collaborates with RBX2 serving as the E3 neddylator, which initiates Cul5 neddylation around the triplet of a lysine residue (Lys724) .…”

“…Thus, in CRC PRDX1 is essential for maintaining intracellular homeostasis by strengthening te UBE2F–Cul5-mediated degradation of NOXA, as shown by CRC cells’ resistance to etoposide therapy. These results suggest that targeting PRDX1 may be a viable approach to overcoming CRC DNA damage resistance …”

“…As several critical molecules that regulate a range of cell activities are the substrates of CRLs, CRLs, and the activation of neddylation consequently play an essential role in many biological mechanisms . Generally, the CRL families subordinate with Cul via some definite transposable substrate receptor molecules . Each receptor molecule can target multiple protein molecules for the ubiquitination reaction.…”

“…Cul5 is a protein that was initially regarded as a vasopressin-activated calcium mobilizing (VACM-1) molecul due to having an arginine vasopressin (AVP) receptor gene in its structure. AVP mainly controls osmoregulation and regulates blood pressure within the body . The current manuscript focuses on a piece of updated information related to the Cul5 substrate’s involvement in various diseases, including cancers and apoptosis, in addition to its involvement in regulating several biological processes.…”