12- O -tetradecanoylphorbol-13-acetate (TPA) increases murine intestinal crypt stem cell survival following radiation injury

// Yaojie Liang 1, * , Hongwei Zhou 1, * , Yibing Yao 1, * , Ailing Deng 2 , Zhihong Wang 1 , Boning Gao 3 , Minhang Zhou 1 , Yu Cui 4 , Lili Wang 5 , Lei Zhou 5 , Bianhong Wang 6 , Li Wang 7 , Anqi Liu 8 , Lanlan Qiu 9 , Kun Qian 6 , Yejian Lu 5 , Wanping Deng 1 , Xi Zheng 1 , Zhengtao Han 10 , Yonghui Li 5 and Junzhong Sun 1 1 Department of Geriatric Oncology, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China 2 Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China 3 Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas, USA 4 State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing, China 5 Department of Hematology, Chinese PLA General Hospital, Beijing, China 6 Department of Hematology, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China 7 Department of Hematology, Laoshan Branch, No.401 Hospital of Chinese PLA, Qingdao, China 8 Department of Critical Care Medicine, Beijing Electric Power Hospital, Capital Medical University, Beijing, China 9 Department of Hematology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China 10 Henan Tumor Research Institute, Zheng Zhou, China * These authors have contributed equally to this work Correspondence to: Junzhong Sun, email: sjunzh07@163.com Yonghui Li, email: yonghuililab@163.com Zhengtao Han, email: hzt-zzhnti@163.com Keywords: 12-O-tetradecanoylphorbol-13-acetate (TPA), intestinal crypt stem cells, radiation injury, IEC-6 cell and BALB/c mouse, radioprotection Received: June 06, 2016     Accepted: March 22, 2017     Published: April 20, 2017 ABSTRACT Radiation enteropathy is a common complication in cancer patients following radiation therapy. Thus, there is a need for agents that can protect the intestinal epithelium against radiation. 12- O -tetradecanoylphorbol-13-acetate (TPA) has been shown to induce differentiation and/or apoptosis in multiple cell lines and primary cells. In the current report, we studied the function of TPA in radiation induced enteropathy in cultured rat intestinal epithelial cell line IEC-6 after ionizing radiation (IR) and in mice after high dose total-body gamma-IR (TBI). In IEC-6 cells, there were reduced apoptosis and cell cycle arrest in TPA treated cells after IR. We detected a four-fold increase in crypt cell survival and a two-fold increase in animal survival post TBI in TPA treated mice. The beneficial effects of TPA were accompanied by upregulation of stem cells markers and higher level of proteins that are involved in PKC signaling pathway. In addition, TPA also decreased the TBI-augmented levels of the DNA damage indicators. The effects were only observed when TPA was given before irradiation. These results suggest that TPA has the ability to modulate intestinal crypt stem cells survival and this may represent a promising countermeasure against radiation induced enteropathy.