xCT contributes to colorectal cancer tumorigenesis through upregulation of the MELK oncogene and activation of the AKT/mTOR cascade.
Amino Acid Transport System y+
/ metabolism
Carcinogenesis
Cell Line, Tumor
Cell Movement
Cell Proliferation
Cell Transformation, Neoplastic
Colorectal Neoplasms
/ metabolism
Gene Expression Regulation, Neoplastic
Humans
Oncogenes
Protein Serine-Threonine Kinases
/ metabolism
Proto-Oncogene Proteins c-akt
/ metabolism
Signal Transduction
TOR Serine-Threonine Kinases
/ genetics
Up-Regulation
/ genetics
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
19 04 2022
19 04 2022
Historique:
received:
22
07
2021
accepted:
04
04
2022
revised:
28
03
2022
entrez:
20
4
2022
pubmed:
21
4
2022
medline:
22
4
2022
Statut:
epublish
Résumé
Colorectal cancer (CRC) is one of the most commonly diagnosed and deadly malignant tumors globally, and its occurrence and progression are closely related to the poor histological features and complex molecular characteristics among patients. It is urgent to identify specific biomarkers for effective treatment of CRC. In this study, we performed comprehensive experiments to validate the role of xCT expression in CRC tumorigenesis and stemness and confirmed xCT knockdown significantly suppressed the proliferation, migration, and stemness of CRC cells in vitro and effectively inhibited CRC tumorigenesis and metastasis in vivo. In addition, bioinformatic analysis and luciferase assays were used to identify E2F1 as a critical upstream transcription factor of SLC7A11 (the gene encoding for xCT) that facilitated CRC progression and cell stemness. Subsequent RNA sequencing, western blotting, rescue assay, and immunofluorescence assays revealed MELK directly co-expressed with xCT in CRC cells, and its upregulation significantly attenuated E2F1/xCT-mediated tumorigenesis and stemness in CRC. Further molecular mechanism exploration confirmed that xCT knockdown may exert an antitumor effect by controlling the activation of MELK-mediated Akt/mTOR signaling. Erastin, a specific inhibitor of xCT, was also proven to effectively inhibit CRC tumorigenesis and cell stemness. Altogether, our study showed that E2F1/xCT is a promising therapeutic target of CRC that promotes tumorigenesis and cell stemness. Erastin is also an effective antitumoral agent for CRC.
Identifiants
pubmed: 35440604
doi: 10.1038/s41419-022-04827-4
pii: 10.1038/s41419-022-04827-4
pmc: PMC9019093
doi:
Substances chimiques
Amino Acid Transport System y+
0
SLC7A11 protein, human
0
MELK protein, human
EC 2.7.1.-
MTOR protein, human
EC 2.7.1.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
373Informations de copyright
© 2022. The Author(s).
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