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Combined targeting of PRDX6 and GSTP1 as a potential differentiation strategy for neuroblastoma treatment

Liaño-Pons, Judit ; Garde-Lapido, Elisa ; Fahrig, Fenja L. ; Jäckering, Merle ; Yuan, Ye ; Andersson, Stina LU ; Schort, Lea ; Esteve, Maria ; Mohlin, Sofie LU orcid and Bedoya-Reina, Oscar C. , et al. (2025) In Proceedings of the National Academy of Sciences of the United States of America 122(25).
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
antioxidants, childhood cancer, differentiation-inducing therapy, neuroblastoma, oxidative stress
in
Proceedings of the National Academy of Sciences of the United States of America
volume
122
issue
25
article number
e2427211122
publisher
National Academy of Sciences
external identifiers
  • pmid:40531876
  • scopus:105009070428
ISSN
0027-8424
DOI
10.1073/pnas.2427211122
language
English
LU publication?
yes
additional info
Publisher Copyright: Copyright © 2025 the Author(s).
id
335e3af2-2302-4ed6-8818-ccb9db25cb9a
date added to LUP
2025-12-15 13:02:09
date last changed
2025-12-15 13:03:19
@article{335e3af2-2302-4ed6-8818-ccb9db25cb9a,
  abstract     = {{<p>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.</p>}},
  author       = {{Liaño-Pons, Judit and Garde-Lapido, Elisa and Fahrig, Fenja L. and Jäckering, Merle and Yuan, Ye and Andersson, Stina and Schort, Lea and Esteve, Maria and Mohlin, Sofie and Bedoya-Reina, Oscar C. and Arsenian-Henrikssona, Marie}},
  issn         = {{0027-8424}},
  keywords     = {{antioxidants; childhood cancer; differentiation-inducing therapy; neuroblastoma; oxidative stress}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{25}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{Combined targeting of PRDX6 and GSTP1 as a potential differentiation strategy for neuroblastoma treatment}},
  url          = {{http://dx.doi.org/10.1073/pnas.2427211122}},
  doi          = {{10.1073/pnas.2427211122}},
  volume       = {{122}},
  year         = {{2025}},
}