Targeting the mitochondrial calcium uniporter inhibits cancer progression and alleviates cisplatin resistance in esophageal squamous cell carcinoma

Miao,Yu; Wang,Xiaofei; Lai,Yafang; Huang,Ying; Yin,Hua; Meng,Xiangkun; Liu,Hao; Hou,Ruirui; Lin,Wan; Zhang,Xiaoxu; Zhang,Xu; Chai,Bei Cho; Zhang,Feixiong; Guo,Le; Yang,Shaoqi

doi:10.3892/ijo.2023.5530

Targeting the mitochondrial calcium uniporter inhibits cancer progression and alleviates cisplatin resistance in esophageal squamous cell carcinoma

Authors:
- Yu Miao
- Xiaofei Wang
- Yafang Lai
- Ying Huang
- Hua Yin
- Xiangkun Meng
- Hao Liu
- Ruirui Hou
- Wan Lin
- Xiaoxu Zhang
- Xu Zhang
- Bei Cho Chai
- Feixiong Zhang
- Le Guo
- Shaoqi Yang
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Affiliations: Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China, Pathology Department, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebie 063000, P.R. China, Department of Gastroenterology, Ordos Central Hospital, Ordos, Inner Mongolia Autonomous Region 017000, P.R. China, Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
Published online on: June 1, 2023 https://doi.org/10.3892/ijo.2023.5530
Article Number: 82
Copyright: © Miao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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 cisplatin‑resistant ESCC cell lines. Then, proliferation, migration, and mitochondrial membrane potential (MMP) were measured by colony formation, wound healing, Transwell, and JC‑1 staining assays. MCU, MICU2, MICU1, and PD‑L1 levels were detected through western blotting and immunofluorescence. ESCC and cisplatin‑resistant ESCC xenograft mouse models were established. After MCU knockdown, tumor volume was measured. The expression levels of proliferation markers (CyclinD1 and Ki‑67), MICU1/2, PD‑L1, epithelial–mesenchymal transition (EMT) markers (vimentin, β‑catenin, and E‑cadherin), 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 cisplatin‑resistant ESCC cells. However, proliferation, migration, and MMP were suppressed following MCU knockdown. In ESCC cells, MCU overexpression markedly increased MICU2, MICU1, and PD‑L1 levels, and the opposite results were observed when MCU was stably knocked down. Similarly, MCU inhibition decreased MICU2, MICU1, and PD‑L1 expression in cisplatin‑resistant ESCC cells. Moreover, MCU knockdown substantially decreased tumor growth, EMT, and angiogenesis in ESCC and cisplatin‑resistant ESCC xenograft mice. Collectively, targeting MCU may inhibit cancer progression and alleviate cisplatin resistance in ESCC.

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