5-Fluorouracil resistance due to sphingosine kinase 2 overexpression in colorectal cancer is associated with myeloid-derived suppressor cell-mediated immunosuppressive effects.
BMC Cancer
; 24(1): 983, 2024 Aug 08.
Article
in En
| MEDLINE
| ID: mdl-39118083
ABSTRACT
PURPOSE:
Colorectal cancer (CRC) is one of the top five cancer-related causes of mortality globally. Acquired resistance has hindered the effectiveness of 5-fluorouracil (5-FU), the main chemotherapeutic drug used to treat CRC. Sphingosine kinase 2 (SphK2) may be a cancer treatment target and involved in 5-FU resistance.METHODS:
Cell growth was examined using MTT and clone formation assays for SphK2 expression. To identify immune cells in mice, flow cytometry was performed. West blotting demonstrated alterations in cell division and inflammation-related proteins. SphK2 levels and inflammation-related variables were studied using Elisa.RESULTS:
Due to SphK2 overexpression, immunosuppression, and 5-FU resistance are caused by the development of myeloid-derived suppressor cells (MDSCs) subsequent to IL-6/STAT3 activation and alterations in the arginase (ARG-1) protein. After therapy, the combination of SphK2 inhibitors and 5-FU can effectively suppress MDSCs while increasing CD4+ and CD8+ T cell infiltration into the tumor microenvironment, lowering tumor burden, and exhibiting a therapeutic impact on CRC.CONCLUSIONS:
Our findings suggest that 5-FU treatment combined with simultaneous Spkh2 inhibition by ABC294640 has anti-tumor synergistic effects by influencing multiple effects on tumor cells, T cells, and MDSCs, potentially improving the poor prognosis of colorectal cancer patients.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Colorectal Neoplasms
/
Phosphotransferases (Alcohol Group Acceptor)
/
Drug Resistance, Neoplasm
/
Fluorouracil
/
Myeloid-Derived Suppressor Cells
Limits:
Animals
/
Humans
Language:
En
Journal:
BMC Cancer
Journal subject:
NEOPLASIAS
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
United kingdom