Blocking cell cycling promotes intestinal stem cell survival after radiotherapy
Radiation therapies that target the abdomen and pelvic regions can result in long-term and lethal complications in rapidly renewing tissue, including the small intestinal epithelium. Thus, the dosage of radiotherapy treatments is limited in part by the damage it causes to intestinal stem cells (ISCs). In mice, high-dose radiotherapy induces DNA damage that rapidly activates the G1/S checkpoint, leading to apoptosis in ISCs. Studies in mammalian cells and yeast have suggested that blocking the G1/S transition can suppress radiation-induced apoptosis and activate DNA repair pathways, but the significance of this approach has not been tested in an in vivo model. Work led by Jian Yu at the University of Pittsburgh School of Medicine has now demonstrated that blocking the G1/S transition with an inhibitor of cyclin-dependent kinase 4/6 (CDK4/6) protected mice against radiation-induced intestinal damage. Treatment with the CDK4/6 inhibitor before and after high-dose irradiation profoundly improved the survival rate of mice and increased intestinal crypt survival and regeneration. These improvements were associated with changes in intestinal proliferation kinetics. In the accompanying image, differences in phosphorylated β-catenin expression (red) at 24-hours and 96-hours after radiation exposure reveal alterations the timing of ISC activation in crypt cells from CDK4/6 inhibitor-treated mice (right images) compared to untreated mice (left images). These findings support the concept that cell cycling regulates the survival of ISCs and indicate that pharmacological quiescence may be an effective strategy for preventing radiotherapy-induced injury in the intestine.
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Abstract
Radiotherapy causes dose-limiting toxicity and long-term complications in rapidly renewing tissues, including the gastrointestinal tract. Currently, there is no FDA-approved agent for the prevention or treatment of radiation-induced intestinal injury. In this study, we have shown that PD 0332991 (PD), an FDA-approved selective inhibitor of cyclin-dependent kinase 4/6 (CDK4/6), prevents radiation-induced lethal intestinal injury in mice. Treating mice with PD or a structurally distinct CDK4/6 inhibitor prior to radiation blocked proliferation and crypt apoptosis and improved crypt regeneration. PD treatment also enhanced LGR5+ stem cell survival and regeneration after radiation. PD was an on-target inhibitor of RB phosphorylation and blocked G1/S transition in the intestinal crypts. PD treatment strongly but reversibly inhibited radiation-induced p53 activation, which blocked p53-upregulated modulator of apoptosis–dependent (PUMA-dependent) apoptosis without affecting p21-dependent suppression of DNA damage accumulation, with a repair bias toward nonhomologous end joining. Further, deletion of
Authors
Liang Wei, Brian J. Leibowitz, Xinwei Wang, Michael Epperly, Joel Greenberger, Lin Zhang, Jian Yu
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ISSN: 0021-9738 (print), 1558-8238 (online)