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ARTICLE

MCU-i4, a mitochondrial Ca2+ uniporter modulator, induces breast cancer BT474 cell death by enhancing glycolysis, ATP production and reactive oxygen species (ROS) burst

EDMUND CHEUNG SO1,2,#, LOUIS W. C. CHOW3,#, CHIN-MIN CHUANG4, CING YU CHEN5,6, CHENG-HSUN WU7, LIAN-RU SHIAO8, TING-TSZ OU9, KAR-LOK WONG10, YUK-MAN LEUNG8,*, YI-PING HUANG8,*
1 Department of Anesthesia, An Nan Hospital, China Medical University, Tainan, 709, Taiwan
2 Graduate Institute of Medical Sciences, Chang Jung Christian University, Tainan, 711301, Taiwan
3 UNIMED Medical Institute, Hong Kong SAR, China
4 Department of Emergency Medicine, China Medical University Hospital, Taichung, 404327, Taiwan
5 Department of Cosmetic Science, Providence University, Taichung, 43301, Taiwan
6 School of Pharmacy, China Medical University, Taichung, 404328, Taiwan
7 Department of Anatomy, China Medical University, Taichung, 404328, Taiwan
8 Department of Physiology, China Medical University, Taichung, 404328, Taiwan
9 Department of Medicinal Botanicals and Healthcare, Dayeh University, Changhua, 51591, Taiwan
10 Department of Anesthesiology, Kuang Tien General Hospital, Shalu, Taichung, 433, Taiwan
* Corresponding Author: YUK-MAN LEUNG. Email: email; YI-PING HUANG. Email: email
# Contributed equally as first authors
(This article belongs to the Special Issue: Recent Advances in Cancer Pharmacology)

Oncology Research https://doi.org/10.32604/or.2024.052743

Received 13 April 2024; Accepted 29 July 2024; Published online 26 August 2024

Abstract

Objectives: Mitochondrial Ca2+ uniporter (MCU) provides a Ca2+ influx pathway from the cytosol into the mitochondrial matrix and a moderate mitochondrial Ca2+ rise stimulates ATP production and cell growth. MCU is highly expressed in various cancer cells including breast cancer cells, thereby increasing the capacity of mitochondrial Ca2+ uptake, ATP production, and cancer cell proliferation. The objective of this study was to examine MCU inhibition as an anti-cancer mechanism. Methods: The effects of MCU-i4, a newly developed MCU inhibitor, on cell viability, apoptosis, cytosolic Ca2+, mitochondrial Ca2+ and potential, glycolytic rate, generation of ATP, and reactive oxygen species, were examined in breast cancer BT474 cells. Results: MCU-i4 caused apoptotic cell death, and it decreased and increased, respectively, mitochondrial and cytosolic Ca2+ concentration. Inhibition of MCU by MCU-i4 revealed that cytosolic Ca2+ elevation resulted from endoplasmic reticulum (ER) Ca2+ release via inositol 1,4,5-trisphosphate receptors (IP3R) and ryanodine receptors (RYR). Unexpectedly, MCU-i4 enhanced glycolysis and ATP production; it also triggered a large production of reactive oxygen species (ROS) and mitochondrial membrane potential collapse. Conclusion: Cytotoxic mechanisms of MCU-i4 in cancer cells involved enhanced glycolysis and heightened formation of ATP and ROS. It is conventionally believed that cancer cell death could be caused by inhibition of glycolysis. Our observations suggest cancer cell death could also be induced by increased glycolytic metabolism.

Keywords

BT474 cells; Breast cancer; MCU-i4; Cell death; Mitochondria Ca2+ uniporter (MCU)

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