Involvement of cardiac glycosides targeting Na/K-ATPase in their inhibitory effects on c-Myc expression via its transcription, translation and proteasomal degradation

• Published in: Journal of biochemistry (Tokyo) Vol. 175; no. 3; p. 253
• Main Authors: Tokugawa, Muneshige, Inoue, Yasumichi, Aoki, Hiromasa, Miyajima, Chiharu, Ishiuchi, Kan'ichiro, Tsurumi, Kento, Kujirai, Chisane, Morishita, Daisuke, Matsuno, Michiyo, Mizukami, Hajime, Ri, Masaki, Iida, Shinsuke, Makino, Toshiaki, Aoyama, Mineyoshi, Hayashi, Hidetoshi
• Format: Journal Article
• Language: English
• Published: England 04.03.2024
• Subjects: Adenosine Triphosphatases; Cardiac Glycosides - pharmacology; Cell Line; Cell Proliferation; Gene Expression Profiling; Humans; α1-Na/K-ATPase.Abbreviations: α1-NKA, α1-Na/K-ATPase; CG, cardiac glycoside; multiple myeloma; cardiac glycosides; periplocin; c-Myc
• ISSN: 1756-2651
• DOI: 10.1093/jb/mvad085

Cardiac glycosides (CGs) have been used for decades to treat heart failure and arrhythmic diseases. Recent non-clinical and epidemiological findings have suggested that CGs exhibit anti-tumor activities. Therefore, CGs may be repositioned as drugs for the treatment of cancer. A detailed understanding of the anti-cancer mechanisms of CGs is essential for their application to the treatment of targetable cancer types. To elucidate the factors associated with the anti-tumor effects of CGs, we performed transcriptome profiling on human multiple myeloma AMO1 cells treated with periplocin, one of the CGs. Periplocin significantly down-regulated the transcription of MYC (c-Myc), a well-established oncogene. Periplocin also suppressed c-Myc expression at the protein levels. This repression of c-Myc was also observed in several cell lines. To identify target proteins for the inhibition of c-Myc, we generated CG-resistant (C9) cells using a sustained treatment with digoxin. We confirmed that C9 cells acquired resistance to the inhibition of c-Myc expression and cell proliferation by CGs. Moreover, the sequencing of genomic DNA in C9 cells revealed the mutation of D128N in α1-Na/K-ATPase, indicating the target protein. These results suggest that CGs suppress c-Myc expression in cancer cells via α1-Na/K-ATPase, which provides further support for the anti-tumor activities of CGs.