title: Computational experiments reveal the efficacy of targeting CDK2 and CKIs for significantly lowering cellular senescence bar for potential cancer treatment.
abstract: Lowering the threshold of cellular senescence, the process employed by cells to thwart abnormal cell proliferation, though inhibition of CDK2 or Skp2 (regulator of CDK inhibitors) has been recently suggested as a potential avenue for cancer treatment. In this study, we employ a published mathematical model of G1/S transition involving the DNA-damage signal transduction pathway to conduct carefully constructed computational experiments to highlight the effectiveness of manipulating cellular senescence in inhibiting damaged cell proliferation. We first demonstrate the suitability of the mathematical model to explore senescence by highlighting the overlap between senescence pathways and those involved in G1/S transition and DNA damage signal transduction. We then investigate the effect of CDK2 deficiency on senescence in healthy cells, followed by effectiveness of CDK2 deficiency in triggering senescence in DNA damaged cells. For this, we focus on the behaviour of CycE, whose peak response indicates G1/S transition, for several reduced CDK2 levels in healthy as well as two DNA-damage conditions to calculate the probability (β) or the percentage of CDK2 deficient cells passing G1/S checkpoint ((1-β) indicates level of senescence). Results show that 50% CDK2 deficiency can cause senescence in all healthy cells in a fairly uniform cell population; whereas, most healthy cells (≈67%) in a heterogeneous population escape senescence. This finding is novel to our study. Under both low- and high-DNA damaged conditions, 50% CDK deficiency can cause 65% increase in senescence in a heterogeneous cell population. Furthermore, the model analyses the relationship between CDK2 and its CKIs (p21, p27) to help search for other effective ways to bring forward cellular senescence. Results show that the degradation rate of p21 and initial concentration of p27 are effective in lowering CDK2 levels to lower the senescence threshold. Specifically, CDK2 and p27 are the most effective in triggering senescence while p21 having a smaller influence. While receiving experimental support, these findings specify in detail the inhibitory effects of CKIs. However, simultaneous variation of CDK2 and CKIs produces a dramatic reduction of damage cells passing the G1/S with CDK2&p27 combination causing senescence in almost all damaged cells. This combined effect of CDK2&CKIs on senescence is a novel contribution in this study. A review of the crucial protein complexes revealed that the concentration of active CycE/CDK2-p that controls cell cycle arrest provides support for the above findings with CycE/CDK2-p undergoing the largest reduction (over 100%) under the combined CDK2&CKI conditions leading to the arrest of most of the damaged cells. Our study thus provides quantitative assessments for the previously published qualitative findings on senescence and highlights new avenues for bringing forward senescence bar.
authors.affiliation: Centre for Advanced Computational Solutions (C-fACS), Molecular Biosciences Department, Lincoln University, Christchurch, New Zealand. Hong.Ling2@lincolnuni.ac.nz
authors.forename: Hong
authors.initials: H
authors.lastname: Ling
authors.forename: Sandhya
authors.initials: S
authors.lastname: Samarasinghe
authors.forename: Don
authors.initials: D
authors.lastname: Kulasiri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D016922:Cellular Senescence / Q000187:drug effects; D003198:Computer Simulation; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods; D004360:Drug Therapy, Computer-Assisted / Q000379:methods; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2