title: Exogenous expression of SAMHD1 inhibits proliferation and induces apoptosis in cutaneous T-cell lymphoma-derived HuT78 cells.
abstract: Sterile α motif and HD domain-containing protein 1 (SAMHD1) is a mammalian dNTP hydrolase (dNTPase) that regulates intracellular dNTP balance. We have previously reported that SAMHD1 mRNA and protein levels are significantly downregulated in CD4+T-cells of patients with cutaneous T-cell lymphoma (CTCL), a disease characterized by infiltration of neoplastic CD4+T-lymphocytes into the skin. However, functional significance of SAMHD1 in CTCL development and progression remains unknown. Here we investigate the mechanism by which SAMHD1 induces apoptosis in CTCL-derived CD4+T-cells. We stably expressed exogenous SAMHD1 in the CTCL-derived HuT78 T-cell line containing a very low level of endogenous SAMHD1 protein. We found that low-level exogenous expression of SAMHD1 led to a significant reduction in HuT78 cell growth, proliferation, and colony formation. Exogenous SAMHD1 expression in HuT78 cells also resulted in increased spontaneous and Fas ligand (Fas-L)-induced apoptosis levels via activation of the extrinsic pathway, including caspase-8, -3 and -7. Additionally, increased SAMHD1 significantly reduced the protein and mRNA expression of the short isoform of cFLIP (cFLIPS), an important negative regulator of Fas-L-mediated apoptotic signaling. Our results indicate that exogenous SAMHD1 expression inhibits HuT78 cell growth and proliferation in part by increasing apoptosis. These findings implicate that SAMHD1 acts as an inhibitor in CTCL cell growth, suggesting that downregulation of SAMHD1 expression in neoplastic T-cells can facilitate uncontrolled cell proliferation.
authors.affiliation: a Center of Retrovirus Research, Department of Veterinary Biosciences ; The Ohio State University , Columbus , OH , USA.
authors.forename: Karthik M
authors.initials: KM
authors.lastname: Kodigepalli
authors.affiliation: a Center of Retrovirus Research, Department of Veterinary Biosciences ; The Ohio State University , Columbus , OH , USA.
authors.forename: Minghua
authors.initials: M
authors.lastname: Li
authors.affiliation: a Center of Retrovirus Research, Department of Veterinary Biosciences ; The Ohio State University , Columbus , OH , USA.
authors.forename: Shan-Lu
authors.initials: SL
authors.lastname: Liu
authors.affiliation: a Center of Retrovirus Research, Department of Veterinary Biosciences ; The Ohio State University , Columbus , OH , USA.|b Comprehensive Cancer Center, The Ohio State University , Columbus , OH , USA.|c Department of Microbial Infection and Immunity , The Ohio State University , Columbus , OH , USA.
authors.forename: Li
authors.initials: L
authors.lastname: Wu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002999:Clone Cells; D053222:Fas Ligand Protein / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000378:metabolism* / Q000473:pathology*; D008954:Models, Biological; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000076106:SAM Domain and HD Domain-Containing Protein 1; D015398:Signal Transduction / Q000187:drug effects; D014410:Tumor Stem Cell Assay
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D053222:Fas Ligand Protein; D012333:RNA, Messenger; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020169:Caspases; D020559:Monomeric GTP-Binding Proteins
keywords: Fas-L; SAMHD1; apoptosis; cFLIP; cell proliferation; lymphoma