SNHG4-mediated PTEN destabilization confers oxaliplatin resistance in colorectal cancer cells by inhibiting ferroptosis.
Apoptosis
; 29(5-6): 835-848, 2024 Jun.
Article
in En
| MEDLINE
| ID: mdl-38573492
ABSTRACT
Oxaliplatin resistance poses a significant challenge in colorectal cancer (CRC) therapy, necessitating further investigation into the underlying molecular mechanisms. This study aimed to elucidate the regulatory role of SNHG4 in oxaliplatin resistance and ferroptosis in CRC. Our findings revealed that treatment with oxaliplatin led to downregulation of SNHG4 expression in CRC cells, while resistant CRC cells exhibited higher levels of SNHG4 compared to parental cells. Silencing SNHG4 attenuated oxaliplatin resistance and reduced the expression of resistance-related proteins MRD1 and MPR1. Furthermore, induction of ferroptosis effectively diminished oxaliplatin resistance in both parental and resistant CRC cells. Notably, ferroptosis induction resulted in decreased SNHG4 expression, whereas SNHG4 overexpression suppressed ferroptosis. Through FISH, RIP, and RNA pull-down assays, we identified the cytoplasmic localization of both SNHG4 and PTEN, establishing that SNHG4 directly targets PTEN, thereby reducing mRNA stability in CRC cells. Silencing PTEN abrogated the impact of SNHG4 on oxaliplatin resistance and ferroptosis in CRC cells. In vivo experiments further validated the influence of SNHG4 on oxaliplatin resistance and ferroptosis in CRC cells through PTEN regulation. In conclusion, SNHG4 promotes resistance to oxaliplatin in CRC cells by suppressing ferroptosis through instability of PTEN, thus serves as a target for patients with oxaliplatin-base chemoresistance.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Colorectal Neoplasms
/
Drug Resistance, Neoplasm
/
PTEN Phosphohydrolase
/
Oxaliplatin
/
Ferroptosis
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Apoptosis
Year:
2024
Document type:
Article
Affiliation country: