Abstract
Heavy ion beams have advantages over conventional radiation in radiotherapy due to their superb biological effectiveness and dose conformity. However, little information is currently available concerning the cellular and molecular basis for heavy ion radiation-induced autophagy. In this study, human glioblastoma SHG44 and cervical cancer HeLa cells were irradiated with carbon ions of different linear energy transfers (LETs) and X-rays. Our results revealed increased LC3-II and decreased p62 levels in SHG44 and HeLa cells post-irradiation, indicating marked induction of autophagy. The autophagic level of tumor cells after irradiation increased in a LET-dependent manner and was inversely correlated with the sensitivity to radiations of various qualities. Furthermore, we demonstrated that high-LET carbon ions stimulated the unfolded protein response (UPR) and mediated autophagy via the UPR-eIF2α-CHOP-Akt signaling axis. High-LET carbon ions more severely inhibited Akt-mTOR through UPR to effectively induce autophagy. Thus, the present data could serve as an important radiobiological basis to further understand the molecular mechanisms by which high-LET radiation induces cell death.
Highlights
Many efforts have been made to decipher the molecular mechanisms by which high-linear energy transfer (LET) radiation induces cell death in cancer cells
We found that carbon ions could effectively elicit autophagy flux in tumor cells, and the autophagic level increased in a LET-dependent manner[12]
To monitor the autophagic flux induced by the carbon ions, we co-treated both cell lines with radiation and chloroquine (CQ) (10 μ M), which blocks the downstream steps of autophagy
Summary
Many efforts have been made to decipher the molecular mechanisms by which high-LET radiation induces cell death in cancer cells. We and others have already reported high-LET carbon ion-induced autophagy in tumor cells[10,11,12]. We found that carbon ions could effectively elicit autophagy flux in tumor cells, and the autophagic level increased in a LET-dependent manner[12]. We investigated the dependence of autophagy on the LET of radiation. The molecular mechanisms of the autophagy response to different LET radiations in diverse signaling pathways were explored. In the present study, we revealed why autophagic levels increase in a LET-dependent manner in irradiated tumor cells
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