Lanatoside C suppressed colorectal cancer cell growth by inducing mitochondrial dysfunction and increased radiation sensitivity by impairing DNA damage repair
- Authors
- Kang, Mi Ae; Kim, Mi-Sook; Kim, Wonwoo; Um, Jee-Hyun; Shin, Young-Joo; Song, Jie-Young; Jeong, Jae-Hoon
- Issue Date
- 2-Feb-2016
- Publisher
- IMPACT JOURNALS LLC
- Keywords
- lanatoside C; autophagy; mitochondria; DNA damage repair; radiosensitivity
- Citation
- ONCOTARGET, v.7, no.5, pp.6074 - 6087
- Journal Title
- ONCOTARGET
- Volume
- 7
- Number
- 5
- Start Page
- 6074
- End Page
- 6087
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/8559
- DOI
- 10.18632/oncotarget.6832
- ISSN
- 1949-2553
- Abstract
- Cardiac glycosides are clinically used for cardiac arrhythmias. In this study, we investigated the mechanism responsible for anti-cancer and radiosensitizing effects of lanatoside C in colorectal cancer cells. Lanatoside C-treated cells showed classic patterns of autophagy, which may have been caused by lanatoside C-induced mitochondrial aggregation or degeneration. This mitochondrial dysfunction was due to disruption of K+ homeostasis, possibly through inhibition of Na+/K+-ATPase activity. In addition, lanatoside C sensitized HCT116 cells (but not HT-29 cells) to radiation in vitro. gamma-H2AX, a representative marker of DNA damage, were sustained longer after combination of irradiation with lanatoside C, suggesting lanatoside C impaired DNA damage repair processes. Recruitment of 53BP1 to damaged DNA, a critical initiation step for DNA damage repair signaling, was significantly suppressed in lanatoside C-treated HCT116 cells. This may have been due to defects in the RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A that increases 53BP1 recruitment to DNA damage sites. Although lanatoside C alone reduced tumor growth in the mouse xenograft tumor model, combination of lanatoside C and radiation inhibited tumor growth more than single treatments. Thus, lanatoside C could be a potential molecule for anti-cancer drugs and radiosensitizing agents.
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