Doxorubicin-mediated apoptosis in glioma cells requires NFAT3.
Nuclear factor of activated T cells (NFAT), a family of transcription factors, has been implicated in many cellular processes, including some cancers. Here, we characterize, for the first time, the role of NFAT3 in doxorubicin (DOX)-mediated apoptosis, migration, and invasion in SNB19 and U87 glioma cells. This study demonstrates that the specific knockdown of NFAT3 results in a dramatic inhibition of the apoptotic effect induced by DOX and favors cell survival. Inhibition of NFAT3 activation by shNFAT3 (shNF3) significantly downregulated tumor necrosis factor (TNF)-alpha induction, its receptor TNFR1, caspase 10, caspase 3, and poly (ADP-ribose) polymerase, abrogating DOX-mediated apoptosis in glioma cells. DOX treatment resulted in NFAT3 translocation to the nucleus. Similarly, shNF3 treatment in SNB19 and U87 cells reversed DOX-induced inhibition of cell migration and invasion, as determined by wound healing and matrigel invasion assays. Taken together, these results indicate that NFAT3 is a prerequisite for the induction of DOX-mediated apoptosis in glioma cells.
Department of Cancer Biology and Pharmacology, College of Medicine at Peoria, University of Illinois, 1649 Peoria, IL 61656, USA.
Sreelatha
S
Gopinath
Sravan K
SK
Vanamala
Meena
M
Gujrati
Jeffrey D
JD
Klopfenstein
Dzung H
DH
Dinh
Jasti S
JS
Rao
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053455:Caspase 10 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D016193:G1 Phase / Q000187:drug effects; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D050778:NFATC Transcription Factors; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; D011065:Poly(ADP-ribose) Polymerases; D053455:Caspase 10; D053148:Caspase 3