Mechanisms of radiation toxicity in transformed and non-transformed cells

Abstract

Radiation damage to biological systems is determined by the type of radiation, the total dosage of exposure, the dose rate, and the region of the body exposed. Three modes of cell death-necrosis, apoptosis, and autophagy-as well as accelerated senescence have been demonstrated to occur in vitro and in vivo in response to radiation in cancer cells as well as in normal cells. The basis for cellular selection for each mode depends on various factors including the specific cell type involved, the dose of radiation absorbed by the cell, and whether it is proliferating and/or transformed. Here we review the signaling mechanisms activated by radiation for the induction of toxicity in transformed and normal cells. Understanding the molecular mechanisms of radiation toxicity is critical for the development of radiation countermeasures as well as for the improvement of clinical radiation in cancer treatment.

Figure 1

Molecular responses to ionizing radiation (IR) in exposed cells. Depending on dose and radiosensitivity of the exposed cell, IR may induce cell death (through apoptosis or necrosis) or trigger accelerated senescence. Increased expression of p53, coupled to various post-translational modifications (e.g., phosphorylation (P), acetylation (Ac)), is a critical step in mediating the cellular response to IR-induced DNA damage. Accelerated senescence can result from p53-dependent induction of p21/waf1 or upregulation of other cell cycle inhibitory proteins (e.g., p16 INK4a). p53 activation also triggers de novo synthesis of pro-apoptotic molecules that mediate intrinsic (e.g., Bax, Puma) or extrinsic (e.g., Fas) apoptotic cell death (red arrows, p53-dependent). Intrinsic apoptosis is governed by Bcl-2 family proteins that regulate mitochondrial outer membrane permeabilization (MOMP), whereas extrinsic apoptosis is signaled through dedicated death receptors (DRs) such as Fas. Both forms of apoptosis rely on the assembly of large multiprotein platforms, including the apoptosome and death-inducing signaling complex (DISC), which facilitate caspase activation through recruitment, dimerization and autocatalytic cleavage. Separate protein complexes containing RIP-1 and/or RIP-3 (e.g., necrosome) can trigger programmed necrosis under certain conditions (e.g., caspase-8 inhibition). IR can also elicit ER stress and autophagy in response to the accumulation of oxidized or misfolded proteins, which may in turn induce apoptosis. Finally, apoptosis may also be triggered by increased ceramide levels, generated through direct IR-induced activation of sphingomyelinases (SMases) in the plasma membrane.