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Targeting PKLR/MYCN/ROMO1 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer.

Publication ,  Journal Article
Chen, W-Y; Thuy Dung, PV; Yeh, H-L; Chen, W-H; Jiang, K-C; Li, H-R; Chen, Z-Q; Hsiao, M; Huang, J; Wen, Y-C; Liu, Y-N
Published in: Redox Biol
June 2023

Conventional treatment of prostate cancer (PCa) uses androgen-deprivation therapy (ADT) to inhibit androgen receptor (AR) signaling-driven tumor progression. ADT-induced PCa recurrence may progress to an AR-negative phenotype with neuroendocrine (NE) histologic features, which are associated with metabolic disturbances and poor prognoses. However, the metabolic pathways that regulate NE differentiation (NED) in PCa remain unclear. Herein, we show a regulatory mechanism in NED-associated metabolism dysfunction induced by ADT, whereby overexpression of pyruvate kinase L/R (PKLR) mediates oxidative stress through upregulation of reactive oxygen species modulator 1 (ROMO1), thereby promoting NED and aggressiveness. ADT mediates the nuclear translocation of PKLR, which binds to the MYCN/MAX complex to upregulate ROMO1 and NE-related genes, leading to altered mitochondrial function and NED of PCa. Targeting nuclear PKLR/MYCN using bromodomain and extra-terminal motif (BET) inhibitors has the potential to reduce PKLR/MYCN-driven NED. Abundant ROMO1 in serum samples may provide prognostic information in patients with ADT. Our results suggest that ADT resistance leads to upregulation of PKLR/MYCN/ROMO1 signaling, which may drive metabolic reprogramming and NED in PCa. We further show that increased abundance of serum ROMO1 may be associated with the development of NE-like PCa.

Duke Scholars

Published In

Redox Biol

DOI

EISSN

2213-2317

Publication Date

June 2023

Volume

62

Start / End Page

102686

Location

Netherlands

Related Subject Headings

  • Signal Transduction
  • Pyruvate Kinase
  • Prostatic Neoplasms, Castration-Resistant
  • Prostatic Neoplasms
  • N-Myc Proto-Oncogene Protein
  • Mitochondrial Proteins
  • Membrane Proteins
  • Male
  • Humans
  • Cell Line, Tumor
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Chen, W.-Y., Thuy Dung, P. V., Yeh, H.-L., Chen, W.-H., Jiang, K.-C., Li, H.-R., … Liu, Y.-N. (2023). Targeting PKLR/MYCN/ROMO1 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer. Redox Biol, 62, 102686. https://doi.org/10.1016/j.redox.2023.102686
Chen, Wei-Yu, Phan Vu Thuy Dung, Hsiu-Lien Yeh, Wei-Hao Chen, Kuo-Ching Jiang, Han-Ru Li, Zi-Qing Chen, et al. “Targeting PKLR/MYCN/ROMO1 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer.Redox Biol 62 (June 2023): 102686. https://doi.org/10.1016/j.redox.2023.102686.
Chen W-Y, Thuy Dung PV, Yeh H-L, Chen W-H, Jiang K-C, Li H-R, et al. Targeting PKLR/MYCN/ROMO1 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer. Redox Biol. 2023 Jun;62:102686.
Chen, Wei-Yu, et al. “Targeting PKLR/MYCN/ROMO1 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer.Redox Biol, vol. 62, June 2023, p. 102686. Pubmed, doi:10.1016/j.redox.2023.102686.
Chen W-Y, Thuy Dung PV, Yeh H-L, Chen W-H, Jiang K-C, Li H-R, Chen Z-Q, Hsiao M, Huang J, Wen Y-C, Liu Y-N. Targeting PKLR/MYCN/ROMO1 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer. Redox Biol. 2023 Jun;62:102686.
Journal cover image

Published In

Redox Biol

DOI

EISSN

2213-2317

Publication Date

June 2023

Volume

62

Start / End Page

102686

Location

Netherlands

Related Subject Headings

  • Signal Transduction
  • Pyruvate Kinase
  • Prostatic Neoplasms, Castration-Resistant
  • Prostatic Neoplasms
  • N-Myc Proto-Oncogene Protein
  • Mitochondrial Proteins
  • Membrane Proteins
  • Male
  • Humans
  • Cell Line, Tumor