Computational Modeling of Signaling Pathways Mediating Cell Cycle Checkpoint Control and Apoptotic Responses to Ionizing Radiation-Induced DNA Damage

Abstract

Rory B. Conolly ᮀ Hamner Institutes for Health Sciences, USA and US EPA ᮀ The shape of dose response of ionizing radiation (IR) induced cancer at low dose region, either linear non-threshold or J-shaped, has been a debate for a long time. This dose response relationship can be influenced by built-in capabilities of cells that minimize the fixation of IR-mediated DNA damage as pro-carcinogenic mutations. Key capabilities include sensing of damage, activation of cell cycle checkpoint arrests that provide time needed for repair of the damage as well as apoptosis. Here we describe computational modeling of the signaling pathways that link sensing of DNA damage and checkpoint arrest activation/apoptosis to investigate how these molecular-level interactions influence the dose response relationship for IR induced cancer. The model provides qualitatively accurate descriptions of the IR-mediated activation of cell cycle checkpoints and the apoptotic pathway, and of time-course activities and dose response of relevant regulatory proteins (e.g. p53 and p21). Linking to a two-stage clonal growth cancer model, the model described here successfully captured a monotonically increasing to a J-shaped dose response curve and identified one potential mechanism leading to the J-shape: the cell cycle checkpoint arrest time saturates with the increase of the dose.

Systems Cancer Biology and the Controlling Mechanisms for the J-Shaped Cancer dose Response: Towards Relaxing the LNT Hypothesis

“…The biological mechanism leading to the J-shaped dose response was identified as saturation of the checkpoint arrest time: The induced checkpoint arrest time is longer per unit of IR dose in the low dose region than that in the high dose region. It is consistent with how toxicologists intuitively perceive bi-phasic hormetic phenomena (detailed review of previous work of model development can be found in Ricci, 2010 andZhao et al, 2012).…”

“…Adopting these mechanisms, we developed our first generation IRinduced cancer dose response relationship model based on systems biology approach (Zhao and Ricci, 2010;Zhao et al, 2012). The signaling I.…”

“…In the earlier modeling (Zhao and Ricci, 2010;Zhao et al, 2012), m is introduced through a logistic function of time t. The relationship between the two propositions A and B (A: the saturation of critical m according to linear increase of IR; B: the saturation of time t according to linear increase of IR) is that A satisfies B. Therefore, if A is true, a Jshaped dose response can occur.…”

Anti-tumor effect of α-pinene on human hepatoma cell lines through inducing G2/M cell cycle arrest

“…While cell growth is normally restrained by the control of cell cycle, cell division cycle is under the regulation of the Cdk family of serin/threonine kinase and cyclins. G2/M transition is regulated by CyclinB1/CDC2 complex in mammalian cells (13,14), and the activity of this complex is regulated by many factors. For example, dual specificity phosphatase CDC25C activates CDC2 via upholding phosphorylation on the Thr14 and Tyr15 of CDC2 (15).…”

Cathepsin L suppression increases the radiosensitivity of human glioma U251 cells via G2/M cell cycle arrest and DNA damage

“…Cell cycle checkpoints are another defense mechanism to protect cells from DNA damage. Many anticancer agents and radiotherapy treatments regulate cancer cell growth via cell cycle arrest at G 0 /G 1 , S, or G 2 /M phases, and then induce apoptotic cell death [46][47][48][49] . Previous studies have indicated that various anticancer drugs and radiotherapy treatments induce cell cycle arrest at the G 2 /M phase [50,51] .…”