2025-06-16 カロリンスカ研究所
<関連情報>
- https://news.ki.se/new-strategy-for-the-treatment-of-severe-childhood-cancer
- https://www.pnas.org/doi/10.1073/pnas.2427211122
神経芽腫治療のための分化戦略としてのPRDX6とGSTP1の複合標的化 Combined targeting of PRDX6 and GSTP1 as a potential differentiation strategy for neuroblastoma treatment
Judit Liaño-Pons, Elisa Garde-Lapido, Fenja L. Fahrig, +7 , and Marie Arsenian-Henriksson
Proceedings of the National Academy of Sciences Published:June 18, 2025
DOI:https://doi.org/10.1073/pnas.2427211122
Significance
Neuroblastoma (NB), an embryonal tumor of the sympathetic nervous system, accounts for 15% of childhood cancer-related deaths. These tumors depend on antioxidant systems to withstand the high oxidative stress caused by their active metabolism. Here, we have identified the antioxidant enzymes peroxiredoxin 6 (PRDX6) and glutathione S-transferase Pi 1 (GSTP1) as promising therapeutic targets in NB. Inhibiting PRDX6 and GSTP1 impairs proliferation and induces functional neural differentiation through molecular pathways different from the current standard-of-care, retinoic acid (RA). Since many patients either fail to respond or develop resistance to RA, identifying alternative strategies to induce differentiation is critical to improve patient outcomes.
Abstract
Neuroblastoma (NB) is a heterogeneous childhood cancer, characterized by the amplification of the MYCN oncogene in 40% of the high-risk cases. Our previous work demonstrated that MYCN drives metabolic reprogramming in NB, including upregulation of antioxidant enzymes. Here, we identify peroxiredoxin 6 (PRDX6) as a promising therapeutic target in NB. Pharmacological inhibition of PRDX6 reduces MYCN levels, induces apoptosis, and promotes neuronal differentiation accompanied by lipid droplet accumulation, essential for the phenotypic reprogramming. Moreover, combined inhibition of PRDX6 and glutathione S-transferase Pi 1 (GSTP1), a key antioxidant enzyme needed for PRDX6 activation, demonstrated synergistic effects both in vitro and in vivo. This strategy results in neuronal maturation as well as activity and initiates downstream pathways distinct from the ones triggered by retinoic acid, the differentiation-inducing agent currently used in clinical practice for NB. Notably, both PRDX6 and GSTP1 are highly expressed in the developing murine adrenal gland, as well as in high-risk, MYCN-amplified NB, correlating with an undifferentiated state and poor prognosis. Together, our results provide insights into the potential of PRDX6 and GSTP1 as therapeutic targets for differentiation induction for children with NB.
