Journal article
SAMHD1 modulates in vitro proliferation of acute myeloid leukemia-derived THP-1 cells through the PI3K-Akt-p27 axis
Cell cycle (Georgetown, Tex.), Vol.17(9), pp.1124-1137
2018
DOI: 10.1080/15384101.2018.1480218
PMCID: PMC6110597
PMID: 29911928
Abstract
Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a mammalian dNTP hydrolase that acts as a negative regulator in the efficacy of cytarabine treatment against acute myeloid leukemia (AML). However, the role of SAMHD1 in AML development and progression remains unknown. We have reported that SAMHD1 knockout (KO) in the AML-derived THP-1 cells results in enhanced proliferation and reduced apoptosis, but the underlying mechanisms are unclear. Here we show that SAMHD1 KO in THP-1 cells increased PI3K activity and reduced expression of the tumor suppressor PTEN. Pharmacological inhibition of PI3K activity reduced cell proliferation specifically in SAMHD1 KO cells, suggesting that SAMHD1 KO-induced cell proliferation is mediated via enhanced PI3K signaling. However, PI3K inhibition did not significantly affect SAMHD1 KO-reduced apoptosis, implicating the involvement of additional mechanisms. SAMHD1 KO also led to enhanced phosphorylation of p27 at residue T157 and its mis-localization to the cytoplasm. Inhibition of PI3K activity reversed these effects, indicating that SAMHD1 KO-induced changes in p27 phosphorylation and localization is mediated via PI3K-Akt signaling. While SAMHD1 KO significantly enhanced THP-1 cell migration in vitro, SAMHD1 KO attenuated the ability of THP-1 cells to form subcutaneous tumors in xenografted immunodeficient mice. This effect correlated with significantly increased expression of tumor necrosis factor α (TNF-α) in tumors, which may suggest that TNF-α-mediated inflammation could account for the decreased tumorigenicity in vivo. Our findings implicate that SAMHD1 can regulate AML cell proliferation via modulation of the PI3K-Akt-p27 signaling axis, and that SAMHD1 may affect tumorigenicity by downregulating inflammation.
Details
- Title: Subtitle
- SAMHD1 modulates in vitro proliferation of acute myeloid leukemia-derived THP-1 cells through the PI3K-Akt-p27 axis
- Creators
- Karthik M Kodigepalli - b Center for Cardiovascular Research , Nationwide Children's Hospital Research Institute , Columbus , OH , USASerena Bonifati - a Center of Retrovirus Research, Department of Veterinary Biosciences , The Ohio State University , Columbus , OH , USANagaraja Tirumuru - a Center of Retrovirus Research, Department of Veterinary Biosciences , The Ohio State University , Columbus , OH , USALi Wu - d Comprehensive Cancer Center , The Ohio State University , Columbus , OH , USA
- Resource Type
- Journal article
- Publication Details
- Cell cycle (Georgetown, Tex.), Vol.17(9), pp.1124-1137
- Publisher
- United States
- DOI
- 10.1080/15384101.2018.1480218
- PMID
- 29911928
- PMCID
- PMC6110597
- ISSN
- 1538-4101
- eISSN
- 1551-4005
- Grant note
- P30 CA016058 / NCI NIH HHS R01 AI104483 / NIAID NIH HHS R01 AI120209 / NIAID NIH HHS R01 GM128212 / NIGMS NIH HHS
- Language
- English
- Date published
- 2018
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984001107802771
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