Targeting the mitochondrial calcium uniporter inhibits cancer progression and alleviates cisplatin resistance in esophageal squamous cell carcinoma.
Int J Oncol
; 63(1)2023 Jul.
Article
in En
| MEDLINE
| ID: mdl-37264968
ABSTRACT
Cisplatin is the standard chemotherapeutic drug used for the treatment of esophageal squamous cell carcinoma (ESCC). Acquired cisplatin resistance is the primary obstacle to prolonging patient survival time. Here, the therapeutic effects of mitochondrial calcium uniporter (MCU) inhibition on tumor growth and cisplatin resistance in ESCC were assessed. MCU was stably overexpressed or knocked down in three ESCC cell lines and three cisplatinresistant ESCC cell lines. Then, proliferation, migration, and mitochondrial membrane potential (MMP) were measured by colony formation, wound healing, Transwell, and JC1 staining assays. MCU, MICU2, MICU1, and PDL1 levels were detected through western blotting and immunofluorescence. ESCC and cisplatinresistant ESCC xenograft mouse models were established. After MCU knockdown, tumor volume was measured. The expression levels of proliferation markers (CyclinD1 and Ki67), MICU1/2, PDL1, epithelial-mesenchymal transition (EMT) markers (vimentin, ßcatenin, and Ecadherin), and the angiogenesis marker CD34 were detected through western blotting, immunohistochemistry, or immunofluorescence. The results showed that MCU overexpression significantly promoted proliferation, migration, and MMP in ESCC cells and cisplatinresistant ESCC cells. However, proliferation, migration, and MMP were suppressed following MCU knockdown. In ESCC cells, MCU overexpression markedly increased MICU2, MICU1, and PDL1 levels, and the opposite results were observed when MCU was stably knocked down. Similarly, MCU inhibition decreased MICU2, MICU1, and PDL1 expression in cisplatinresistant ESCC cells. Moreover, MCU knockdown substantially decreased tumor growth, EMT, and angiogenesis in ESCC and cisplatinresistant ESCC xenograft mice. Collectively, targeting MCU may inhibit cancer progression and alleviate cisplatin resistance in ESCC.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Esophageal Neoplasms
/
Carcinoma, Squamous Cell
/
Esophageal Squamous Cell Carcinoma
Limits:
Animals
/
Humans
Language:
En
Journal:
Int J Oncol
Year:
2023
Document type:
Article