Journal article
SAMHD1 inhibits epithelial cell transformation in vitro and affects leukemia development in xenograft mice
Cell cycle (Georgetown, Tex.), Vol.17(23), pp.2564-2576
12/04/2018
DOI: 10.1080/15384101.2018.1550955
PMCID: PMC6300106
PMID: 30474474
Abstract
Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a mammalian dNTP hydrolase (dNTPase) and functions as a negative regulator in the efficacy of cytarabine treatment of acute myeloid leukemia (AML). We have reported that SAMHD1 knockout (KO) increased the activity of phosphoinositide 3-kinase (PI3K) in AML-derived THP-1 cells and attenuated their ability to form subcutaneous tumors in xenografted immunodeficient mice. However, the functional significance of SAMHD1 in controlling AML leukemogenesis remains unclear. Previous studies show that
in vitro
transformation of Madin-Darby canine kidney (MDCK) epithelial cells by the Jaagsiekte sheep retrovirus (JSRV) envelope protein requires activation of the PI3K/Akt oncogenic signaling pathway. Using this cell transformation model, we demonstrated that ectopic expression of wild-type human SAMHD1 or a dNTPase-defective SAMHD1 mutant (HD/AA) significantly inhibited MDCK cell transformation, but did not affect cell proliferation. To visualize and quantify THP-1 cell growth and metastasis in xenografted immunodeficient mice, we generated luciferase-expressing stable SAMHD1 KO THP-1 cells and control THP-1 cells, which were injected intravenously into immunodeficient mice. Bioluminescence imaging and quantification analysis of xenografted mice revealed that SAMHD1 KO cell-derived tumors had similar growth and metastatic potential compared with control cells at 35 days post-injection. However, mice xenografted with SAMHD1 KO cells showed greater survival compared with mice injected with control cells. Our data suggest that exogenous SAMHD1 expression suppresses
in vitro
cell transformation independently of its dNTPase activity, and that endogenous SAMHD1 affects AML tumorigenicity and disease progression
in vivo
.
Details
- Title: Subtitle
- SAMHD1 inhibits epithelial cell transformation in vitro and affects leukemia development in xenograft mice
- Creators
- Karthik M Kodigepalli - Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State UniversityMinghua Li - Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State UniversitySerena Bonifati - Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State UniversityAmanda R Panfil - Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State UniversityPatrick L Green - Comprehensive Cancer Center, The Ohio State UniversityShan-Lu Liu - Department of Microbial Infection and Immunity, The Ohio State UniversityLi Wu - Department of Microbial Infection and Immunity, The Ohio State University
- Resource Type
- Journal article
- Publication Details
- Cell cycle (Georgetown, Tex.), Vol.17(23), pp.2564-2576
- Publisher
- Taylor & Francis
- DOI
- 10.1080/15384101.2018.1550955
- PMID
- 30474474
- PMCID
- PMC6300106
- ISSN
- 1538-4101
- eISSN
- 1551-4005
- Grant note
- P30 CA016058 / ; ; AI120209 / ; ;
- Language
- English
- Date published
- 12/04/2018
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984002380202771
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