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Inhibition of CDK4/6 protects against radiation-induced intestinal injury in mice.

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 PUMA synergized with PD treatment for even greater intestinal radioprotection. Our results demonstrate that the cell cycle critically regulates the DNA damage response and survival of intestinal stem cells and support the concept that pharmacological quiescence is a potentially highly effective and selective strategy for intestinal radioprotection.

SUBMITTER: Wei L

PROVIDER: S-EPMC5096907 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Inhibition of CDK4/6 protects against radiation-induced intestinal injury in mice.

Wei Liang L Leibowitz Brian J BJ Wang Xinwei X Epperly Michael M Greenberger Joel J Zhang Lin L Yu Jian J

The Journal of clinical investigation 20161004 11

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 inh ...[more]

PMID: 27701148

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Project description:The histone methyltransferase SET and MYND domain protein 2 (SMYD2) has been implicated in tumorigenesis through methylating histone H3 at lysine36 (H3K36) and some non-histone substrates. Currently, the role of SMYD2 in acute kidney injury (AKI) remains unknown. Here, we investigated the effects of AZ505, a highly selective inhibitor of SMYD2, on the development of AKI and the mechanisms involved in a murine model of cisplatin-induced AKI. SMYD2 and trimethylated histone H3K36 (H3K36Me3) were highly expressed in the kidney following cisplatin treatment; administration of AZ505 remarkedly inhibited their expression, along with improving kidney function and ameliorating kidney damage. AZ505 also attenuated kidney tubular cell injury and apoptosis as evidenced by diminished the expression of neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule (Kim-1), reduced the number of TUNEL positive cells, decreased the expression of cleaved caspase-3 and the BAX/BCL-2 ratio in injured kidneys. Moreover, AZ505 inhibited cisplatin-induced phosphorylation of p53, a key driver of kidney cell apoptosis and reduced expression of p21, a cell cycle inhibitor. Meanwhile, AZ505 promoted expression of proliferating cell nuclear antigen and cyclin D1, two markers of cell proliferation. Furthermore, AZ505 was effective in suppressing the phosphorylation of STAT3 and NF-κB, two transcriptional factors associated with kidney inflammation, attenuating the expression of monocyte chemoattractant protein-1 and intercellular cell adhesion molecule-1 and reducing infiltration of F4/80+ macrophages to the injured kidney. Finally, in cultured HK-2 cells, silencing of SMYD2 by specific siRNA inhibited cisplatin-induced apoptosis of kidney tubular epithelial cells. Collectively, these results suggests that SMYD2 is a key determinant of cisplatin nephrotoxicity and targeting SMYD2 protects against cisplatin-induced AKI by inhibiting apoptosis and inflammation and promoting cell proliferation.

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Inhibition of CDK4/6 protects against radiation-induced intestinal injury in mice.

Publications

Inhibition of CDK4/6 protects against radiation-induced intestinal injury in mice.

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