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Role of autophagy in high linear energy transfer radiation-induced cytotoxicity to tumor cells.

ABSTRACT: Heavy-ion radiotherapy has a potential advantage over conventional radiotherapy due to improved dose distribution and a higher biological effectiveness in cancer therapy. However, there is a little information currently available on the cellular and molecular basis for heavy-ion irradiation-induced cell death. Autophagy, as a novel important target to improve anticancer therapy, has recently attracted considerable attention. In this study, the effect of autophagy induced by high linear energy transfer (LET) carbon ions was examined in various tumor cell lines. To our knowledge, our study is the first to reveal that high-LET carbon ions could induce autophagy in various tumor cells effectively, and the autophagic level in the irradiated cells increased in a dose- and LET-dependent manner. The ability of carbon ions to inhibit the activation of the PI3K/Akt pathway rose with increasing their LET. Moreover, modulation of autophagy in tumor cells could modify their sensitivity to high-LET radiation, and inhibiting autophagy accelerated apoptotic cell death, resulting in an increase in radiosensitivity. Our data imply that targeting autophagy might enhance the effectiveness of heavy-ion radiotherapy.

SUBMITTER: Jin X

PROVIDER: S-EPMC4317928 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Role of autophagy in high linear energy transfer radiation-induced cytotoxicity to tumor cells.

Jin Xiaodong X Liu Yan Y Ye Fei F Liu Xiongxiong X Furusawa Yoshiya Y Wu Qingfeng Q Li Feifei F Zheng Xiaogang X Dai Zhongying Z Li Qiang Q

Cancer science 20140524 7

Heavy-ion radiotherapy has a potential advantage over conventional radiotherapy due to improved dose distribution and a higher biological effectiveness in cancer therapy. However, there is a little information currently available on the cellular and molecular basis for heavy-ion irradiation-induced cell death. Autophagy, as a novel important target to improve anticancer therapy, has recently attracted considerable attention. In this study, the effect of autophagy induced by high linear energy tr ...[more]

PMID: 24731006

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Project description:Heavy ion radiation, prevalent in outer space and relevant for radiotherapy, is densely ionizing and poses a risk to intestinal stem cells (ISCs), which are vital for maintaining intestinal homeostasis. Earlier studies have shown that heavy-ion radiation can cause chronic oxidative stress, persistent DNA damage, cellular senescence, and the development of a senescence-associated secretory phenotype (SASP) in mouse intestinal mucosa. However, the specific impact on different cell types, particularly Lgr5+ intestinal stem cells (ISCs), which are crucial for maintaining cellular homeostasis, GI function, and tumor initiation under genomic stress, remains understudied. Using an ISCs-relevant mouse model (Lgr5+ mice) and its GI tumor surrogate (Lgr5+Apc1638N/+ mice), we investigated ISCs-specific molecular alterations after high-LET radiation exposure. Tissue sections were assessed for senescence and SASP signaling at 2, 5 and 12 months post-exposure. Lgr5+ cells exhibited significantly greater oxidative stress following 28Si irradiation compared to γ-ray or controls. Both Lgr5+ cells and Paneth cells showed signs of senescence and developed a senescence-associated secretory phenotype (SASP) after 28Si exposure. Moreover, gene expression of pro-inflammatory and pro-growth SASP factors remained persistently elevated for up to a year post-28Si irradiation. Additionally, p38 MAPK and NF-κB signaling pathways, which are critical for stress responses and inflammation, were also upregulated after 28Si radiation. Transcripts involved in nutrient absorption and barrier function were also altered following irradiation. In Lgr5+Apc1638N/+ mice, tumor incidence was significantly higher in those exposed to 28Si radiation compared to the spontaneous tumorigenesis observed in control mice. Our results indicate that high-LET 28Si exposure induces persistent DNA damage, oxidative stress, senescence, and SASP in Lgr5+ ISCs, potentially predisposing astronauts to altered nutrient absorption, barrier function, and GI carcinogenesis during and after a long-duration outer space mission.

Dataset Information

Role of autophagy in high linear energy transfer radiation-induced cytotoxicity to tumor cells.

Publications

Role of autophagy in high linear energy transfer radiation-induced cytotoxicity to tumor cells.

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