Abstract
Radiotherapy using high linear energy transfer (LET) radiation results in effectively killing tumor cells while minimizing dose (biological effective) to normal tissues to block toxicity. It is well known that high LET radiation leads to lower cell survival per absorbed dose than low LET radiation. High-linear energy transfer (LET) neutron treatment induces autophagy in tumor cells, but its precise mechanisms in osteosarcoma are unknown. Here, we investigated this mechanism and the underlying signaling pathways. Autophagy induction was examined in gamma-ray-treated KHOS/NP and MG63 osteosarcoma cells along with exposure to high-LET neutrons. The relationship between radiosensitivity and autophagy was assessed by plotting the cell surviving fractions against autophagy levels. Neutron treatment increased autophagy rates in irradiated KHOS/NP and MG63 cells; neutrons with high-LETs showed more effective inhibition than those with lower LET gamma-rays. To determine whether the unfolded protein response and Akt-mTOR pathways triggered autophagy, phosphorylated eIF2α and JNK levels, and phospho-Akt, phosphor-mTOR, and phospho-p70S6 levels were, respectively, investigated. High-LET neutron exposure inhibited Akt phosphorylation and increased Beclin 1 expression during the unfolded protein response, thereby enhancing autophagy. The therapeutic efficacy of high-LET neutron radiation was also assessed in vivo using an orthotopic mouse model. Neutron-irradiated mice showed reduced tumor growth without toxicity relative to gamma-ray-treated mice. The effect of high-LET neutron exposure on the expression of signaling proteins LC3, p-elF2a, and p-JNK was investigated by immunohistochemistry. Tumors in high-LET-neutron radiation-treated mice showed higher apoptosis rates, and neutron exposure significantly elevated LC3 expression, and increased p-elF2a and p-JNK expression levels. Overall, these results demonstrate that autophagy is important in radiosensitivity, cell survival, and cellular resistance against high-LET neutron radiation. This correlation between cellular radiosensitivity and autophagy may be used to predict radiosensitivity in osteosarcoma.
Highlights
Fast neutron therapy (FNT) has been an available cancer radiation treatment since 1976, which is routinely performed
FNT and boron neutron capture therapy utilize the effects of secondary protons and alpha particles, respectively, which have 5–50-fold higher linear energy transfer (LET) than radiation from electron and proton accelerators typically used in hospitals
These findings reveal a correlation between cellular radiosensitivity and autophagy, which may be used to predict radiosensitivity in OS exposed to radiation of different qualities
Summary
Fast neutron therapy (FNT) has been an available cancer radiation treatment since 1976, which is routinely performed. FNT and boron neutron capture therapy utilize the effects of secondary protons and alpha particles, respectively, which have 5–50-fold higher linear energy transfer (LET) than radiation from electron and proton accelerators typically used in hospitals. High-LET radiation differs from low-LET radiation such as photons, electrons, and high-energy (>100 MeV) protons with respect to their high ionization density, effects on the oxygen concentration in cells, and dependence on the cell cycle phase and on cell differentiation. High-LET radiation can sustainably deactivate radioresistant tumor cells. This property yields a slight therapeutic gap with an increased risk of off-target effects on the normal tissue. The most destructive effect of radiation is DNA damage, which blocks cell proliferation
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