Research Papers:

Lanatoside C suppressed colorectal cancer cell growth by inducing mitochondrial dysfunction and increased radiation sensitivity by impairing DNA damage repair

Mi Ae Kang, Mi-Sook Kim, Wonwoo Kim, Jee-Hyun Um, Young-Joo Shin, Jie-Young Song and Jae-Hoon Jeong _

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Oncotarget. 2016; 7:6074-6087. https://doi.org/10.18632/oncotarget.6832

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Mi Ae Kang1, Mi-Sook Kim1,2, Wonwoo Kim1, Jee-Hyun Um3, Young-Joo Shin4, Jie-Young Song5, Jae-Hoon Jeong1

1Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

2Department of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

3Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea

4Department of Radiation Oncology, Inje University Sanggye Paik Hospital, Seoul, Korea

5Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

Correspondence to:

Jae-Hoon Jeong, e-mail: [email protected]

Mi-Sook Kim, e-mail: [email protected]

Keywords: lanatoside C, autophagy, mitochondria, DNA damage repair, radiosensitivity

Received: September 11, 2015    Accepted: December 07, 2015    Published: January 07, 2016


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. γ-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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