Abstract
Radiation-induced bystander effect (RIBE) has important implications for secondary cancer risk assessment during cancer radiotherapy, but the defense and self-protective mechanisms of bystander normal cells are still largely unclear. The present study found that micronuclei (MN) formation could be induced in the non-irradiated HL-7702 hepatocyte cells after being treated with the conditioned medium from irradiated hepatoma HepG2 cells under either normoxia or hypoxia, where the ratio of the yield of bystander MN induction to the yield of radiation-induced MN formation under hypoxia was much higher than that of normoxia. Nonetheless, thapsigargin induced endoplasmic reticulum (ER) stress and dramatically suppressed this bystander response manifested as the decrease of MN and apoptosis inductions. Meanwhile, the interference of BiP gene, a major ER chaperone, amplified the detrimental RIBE. More precisely, thapsigargin provoked ER sensor of PERK to initiate an instantaneous and moderate ER stress thus defensed the hazard form RIBE, while BiP depletion lead to persistently destroyed homeostasis of ER and exacerbated cell injury. These findings provide new insights that the mild ER stress through BiP-PERK-p-eIF2α signaling pathway has a profound role in protecting cellular damage from RIBE and hence may decrease the potential secondary cancer risk after cancer radiotherapy.
Highlights
Self-protective mechanisms of bystander normal cells would be crucial for better understanding of overall cancer risk control
The present study investigated the role of endoplasmic reticulum (ER) stress of hepatocyte cells in the bystander responses induced by irradiated hepatoma cells under normoxic and hypoxic conditions, and found that the moderate ER stress was beneficial for bystander hepatocyte cells to defense against detrimental radiation induced bystander effect (RIBE) from hepatoma cells in alleviating cell injury including DNA damage and cellular apoptosis
Our previous study has shown that RIBE plays a more important role in radiation damage of hepatoma cells under hypoxia than normoxia[21], but it is unclear whether this special contribution of bystander effect exists between hepatoma cells and hepatocyte
Summary
Self-protective mechanisms of bystander normal cells would be crucial for better understanding of overall cancer risk control. The endoplasmic reticulum (ER) is a multifunctional organelle that participates in a variety of signaling pathways for the maintenance of organismal and cellular function and survival[22] This process is tightly supervised by an ER-resident chaperone, termed as immunoglobulin heavy chain binding protein (BiP), which is in charge of maintaining proteins in folding-competent state, ER calcium homeostasis, as well as monitoring the accumulation of unfolded/misfolded proteins[23]. The present study investigated the role of ER stress of hepatocyte cells in the bystander responses induced by irradiated hepatoma cells under normoxic and hypoxic conditions, and found that the moderate ER stress was beneficial for bystander hepatocyte cells to defense against detrimental RIBE from hepatoma cells in alleviating cell injury including DNA damage and cellular apoptosis
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