Involvement of c-Myc in low dose radiation-induced senescence enhanced migration and invasion of unirradiated cancer cells

Abstract

Ionizing radiation is known to cause cell apoptosis at high dose range, but little is known about the cellular response to low dose radiation. In this study, we found that conditioned medium harvested from WI-38 lung fibroblasts and H1299 lung adenocarcinoma cells exposed to 0.1Gy to 1Gy could enhance the migration and invasion of unirradiated H1299 cells in both 2D and 3D culturing circumstances. Low dose radiation did not induce apoptosis, but induced senescence in irradiated cells. We next examined the expression of immediately early genes including c-Myc and K-Ras. Although both genes could be up-regulated by low dose radiation, induction of c-Myc was more specific to low dose range (0.5Gy) at transcriptional and translational levels. Knockdown of c-Myc by shRNA could repress the senescence induced by low dose radiation. The conditioned medium of irradiated cells induced migration of unirradiated cells was also repressed by knockdown of c-Myc. The c-Myc inhibitor 10058-F4 could suppress low dose radiation induced cell senescence, and the conditioned medium harvested from irradiated cells pretreated with 10058-F4 also lost the ability to enhance the migration of unirradiated cells. The cytokine array analysis revealed that immunosuppressive monocyte chemoattractant protein-1 increased by low dose radiation could be repressed by 10058-F4. We also showed that 10058-F4 could suppress low dose radiation induced tumor progression in a xenograft tumor model. Taken together, current data suggest that -Myc is involved in low dose radiation induced cell senescence and potent bystander effect to increase the motility of unirradiated cells.

Radiation-Induced Cellular Senescence Reduces Susceptibility of Glioblastoma Cells to Oncolytic Vaccinia Virus

“…The SASP is a unique characteristic of senescent cells in which a variety of factors including cytokines, chemokines, mitogens, and proteases are secreted and can cause various downstream effects [ 67 ]. The secreted factors from radiation-induced senescent cells generate bystander effects in nearby non-senescent cells [ 68 , 69 , 70 ]. These reports coupled with the observation that, 7 days following irradiation the senescent cell population in the culture was equally resistant to VACV infection as the proliferating population in the same culture ( Figure 3 E), led us to hypothesize that radiation exposure may induce the secretion of antiviral factors that might affect virus replication in nearby non-senescent cells.…”

“…The SASP is a unique characteristic of senescent cells in which a variety of factors including cytokines, chemokines, mitogens, and proteases are secreted and can cause various downstream effects [67]. The secreted factors from radiation-induced senescent cells generate bystander effects in nearby non-senescent cells [68][69][70]. These reports coupled…”

Low-Dose Non-Targeted Effects and Mitochondrial Control

“…Recently, conditioned medium from irradiated WI-38 lung fibroblasts and H1299 lung adenocarcinoma cells exposed to 0.1-1 Gy enhanced the migration and the invasion of unirradiated H1299 cells without inducing apoptosis but senescence in a c-Myc-dependent way [363]. This suggests that the bystander responses can be dependent on the particular oncogenic state of the cells.…”

Primary cilium participates in radiation‐induced bystander effects through TGF‐β1 signaling

“…After decades of research, RIBE has been detected in vitro (Burdak‐Rothkamm et al, 2007; Hu et al, 2014; Iyer et al, 2000; Shao et al, 2008; Xu et al, 2014), in 3D culture tissues (Burdak‐Rothkamm et al, 2007; Leu et al, 2021), and in vivo (Hu et al, 2021; Peng et al, 2017). It was proposed that gap junctional intercellular communication and soluble extracellular factors such as cytokines, reactive oxygen species (ROS), and miRNAs released from irradiated cells participate in the bystander effects (Gao et al, 2021).…”