Role of creatine shuttle in colorectal cancer cells
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Mayu Kita1, Rina Fujiwara-Tani1, Shingo Kishi1, Shiori Mori1, Hitoshi Ohmori1, Chie Nakashima1, Kei Goto1, Takamitsu Sasaki1, Kiyomu Fujii1, Isao Kawahara1, Ujjal Kumar Bhawal2, Yi Luo3 and Hiroki Kuniyasu1
1 Department of Molecular Pathology, Nara Medical University, Kashihara, Nara 634-8521, Japan
2 Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai 600077, India
3 Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China
|Hiroki Kuniyasu,||email:||[email protected]|
|Rina Fujiwara-Tani,||email:||[email protected]|
Keywords: creatine kinase B; mitochondrial creatine kinase; ATP metabolism; phosphorylation signal; stemness
Received: March 01, 2023 Accepted: May 06, 2023 Published: May 19, 2023
The creatine shuttle translocates the energy generated by oxidative phosphorylation to the cytoplasm via mitochondrial creatine kinase (MTCK) and creatine kinase B (CKB) in the cytoplasm. It is not apparent how the creatine shuttle is related to cancer. Here, we analyzed the expression and function of CKB and MTCK in colorectal cancer (CRC) and investigated the role of the creatine shuttle in CRC. Compared with normal mucosa, 184 CRC tissues had higher levels of CKB and MTCK, and these levels were associated with histological grade, tumor invasion, and distant metastasis. CK inhibitor dinitrofluorobenzene (DNFB) on CRC cell lines HT29 and CT26 inhibited cell proliferation and stemness to less than 2/3 and 1/20 of their control levels, respectively. In this treatment, the production of reactive oxygen species increased, mitochondrial respiration decreased, and mitochondrial volume and membrane potential decreased. In a syngeneic BALB/c mouse model using CT26 cells pretreated with DNFB, peritoneal metastasis was suppressed to 70%. Phosphorylation of EGFR, AKT, and ERK1/2 was inhibited in DNFB-treated tumors. High ATP concentrations prevented EGFR phosphorylation in HT29 cells following DNFB treatment, CKB or MTCK knockdown, and cyclocreatine administration. Despite not being immunoprecipitated, CKB and EGFR were brought closer together by EGF stimulation. These findings imply that blocking the creatine shuttle decreases the energy supply, suppresses oxidative phosphorylation, and blocks ATP delivery to phosphorylation signals, preventing signal transduction. These findings highlight the critical role of the creatine shuttle in cancer cells and suggest a potential new cancer treatment target.
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