title: Lanatoside C suppressed colorectal cancer cell growth by inducing mitochondrial dysfunction and increased radiation sensitivity by impairing DNA damage repair.
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. 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.
authors.affiliation: Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Mi Ae
authors.initials: MA
authors.lastname: Kang
authors.affiliation: Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.|Department of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Wonwoo
authors.initials: W
authors.lastname: Kim
authors.affiliation: Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.
authors.forename: Jee-Hyun
authors.initials: JH
authors.lastname: Um
authors.affiliation: Department of Radiation Oncology, Inje University Sanggye Paik Hospital, Seoul, Korea.
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Shin
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Jie-Young
authors.initials: JY
authors.lastname: Song
authors.affiliation: Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Jeong
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007799:Lanatosides / Q000494:pharmacology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D011897:Random Allocation; D015398:Signal Transduction
chemical_list: D007799:Lanatosides; D011838:Radiation-Sensitizing Agents; C018548:lanatoside C
keywords: DNA damage repair; autophagy; lanatoside C; mitochondria; radiosensitivity