The tumour suppressor CCDC6 is involved in ROS tolerance and neoplastic transformation by evading ferroptosis.
DNA DSBs
Deferoxamine
Embryonal carcinoma
Erastin
Ferrostatin-1
Glutathione
Homologous recombination
PARP inhibitors
Seminoma
Targeted therapies
xCT/SLC7A11 cystine antiporter
Journal
Heliyon
ISSN: 2405-8440
Titre abrégé: Heliyon
Pays: England
ID NLM: 101672560
Informations de publication
Date de publication:
Nov 2021
Nov 2021
Historique:
received:
12
07
2021
revised:
11
10
2021
accepted:
11
11
2021
entrez:
29
11
2021
pubmed:
30
11
2021
medline:
30
11
2021
Statut:
epublish
Résumé
Coiled-coil domain containing 6 (CCDC6) is a tumour suppressor gene involved in apoptosis and DNA damage response. CCDC6 is known to be functionally impaired upon gene fusions, somatic mutations, and altered protein turnover in several tumours. Testicular germ cell tumours are among the most common malignancies in young males. Despite the high cure rate, achieved through chemotherapy and/or surgery, drug resistance can still occur. In a human cellular model of testis Embryonal Carcinoma, the deficiency of CCDC6 was associated with defects in DNA repair via homologous recombination and sensitivity to PARP1/2 inhibitors. Same data were obtained in a panel of murine testicular cell lines, including Sertoli, Spermatogonia and Spermatocytes. In these cells, upon oxidative damage exposure, the absence of CCDC6 conferred tolerance to reactive oxygen species affecting regulated cell death pathways by apoptosis and ferroptosis. At molecular level, the loss of CCDC6 was associated with an enhancement of the xCT/SLC7A11 cystine antiporter expression which, by promoting the accumulation of ROS, interfered with the activation of ferroptosis pathway. In conclusion, our data suggest that the CCDC6 downregulation could aid the testis germ cells to be part of a pro-survival pathway that helps to evade the toxic effects of endogenous oxidants contributing to testicular neoplastic growth. Novel therapeutic options will be discussed.
Identifiants
pubmed: 34841108
doi: 10.1016/j.heliyon.2021.e08399
pii: S2405-8440(21)02502-0
pmc: PMC8605351
doi:
Types de publication
Journal Article
Langues
eng
Pagination
e08399Informations de copyright
© 2021 The Authors. Published by Elsevier Ltd.
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
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