Context-dependent roles for ubiquitous mitochondrial creatine kinase CKMT1 in breast cancer progression

Vinay Ayyappan; Nicole M Jenkinson; Caitlin M Tressler; Zheqiong Tan; Menglin Cheng; Xinyi Elaine Shen; Alejandro Guerrero; Kanchan Sonkar; Ruoqing Cai; Oluwatobi Adelaja; Sujayita Roy; Alan Meeker; Pedram Argani; Kristine Glunde

doi:10.1016/j.celrep.2024.114121

Context-dependent roles for ubiquitous mitochondrial creatine kinase CKMT1 in breast cancer progression

Cell Rep. 2024 Apr 23;43(4):114121. doi: 10.1016/j.celrep.2024.114121. Epub 2024 Apr 12.

Affiliations

¹ Johns Hopkins University In Vivo Cellular and Molecular Imaging Center, Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Johns Hopkins University In Vivo Cellular and Molecular Imaging Center, Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Medical Laboratory, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Johns Hopkins University In Vivo Cellular and Molecular Imaging Center, Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: kglunde@mri.jhu.edu.

PMID: 38615320
DOI: 10.1016/j.celrep.2024.114121

Abstract

Metabolic reprogramming is a hallmark of cancer, enabling cancer cells to rapidly proliferate, invade, and metastasize. We show that creatine levels in metastatic breast cancer cell lines and secondary metastatic tumors are driven by the ubiquitous mitochondrial creatine kinase (CKMT1). We discover that, while CKMT1 is highly expressed in primary tumors and promotes cell viability, it is downregulated in metastasis. We further show that CKMT1 downregulation, as seen in breast cancer metastasis, drives up mitochondrial reactive oxygen species (ROS) levels. CKMT1 downregulation contributes to the migratory and invasive potential of cells by ROS-induced upregulation of adhesion and degradative factors, which can be reversed by antioxidant treatment. Our study thus reconciles conflicting evidence about the roles of metabolites in the creatine metabolic pathway in breast cancer progression and reveals that tight, context-dependent regulation of CKMT1 expression facilitates cell viability, cell migration, and cell invasion, which are hallmarks of metastatic spread.

Keywords: CKMT1; CP: Cancer; CP: Metabolism; breast cancer; creatine; metabolism; metastasis; reactive oxygen species.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast Neoplasms* / genetics
Breast Neoplasms* / metabolism
Breast Neoplasms* / pathology
Cell Line, Tumor
Cell Movement
Cell Survival
Creatine Kinase
Creatine Kinase, Mitochondrial Form* / metabolism
Disease Progression
Female
Gene Expression Regulation, Neoplastic
Humans
Mice
Mitochondria / metabolism
Neoplasm Invasiveness
Neoplasm Metastasis
Reactive Oxygen Species* / metabolism

Substances

CKMT1A protein, human
Creatine Kinase
Creatine Kinase, Mitochondrial Form
Reactive Oxygen Species