Stat3, a member of the signal transducers and activators of transcription (STAT) family, is a key signal transduction
protein activated by numerous
cytokines,
growth factors, and
oncoproteins that controls cell proliferation, differentiation, development, survival, and
inflammation. Constitutive activation of Stat3 has been found frequently in a wide variety of human
tumors and induces cellular transformation and
tumor formation. In this study, we demonstrated that LIGHT, a member of
tumor necrosis factor superfamily, activates Stat3 in
cancer cells. LIGHT induces dose-dependent activation of Stat3 by phosphorylation at both the
tyrosine 705 and
serine 727 residues. The activation of Stat3 by LIGHT appears to be mediated by NIK phosphorylation. Expression of a
kinase-inactive NIK mutant abolished LIGHT induced Stat3 activation. Overexpression of an active NIK induces Stat3 activation by phosphorylation at the both
tyrosine 705 and
serine 727 residues. Activation of Stat3 by NIK requires NIK
kinase activity as showed by
kinase assays. In addition, LIGHT increases the expression of Stat3 target genes including
cyclin D1,
survivin, and Bcl-xL, and stimulates human LNCaP
prostate cancer cell growth in vitro which can be blocked by expression of a dominant-negative Stat3 mutant. Taken together, these results indicate that in addition to activating
NF-kappaB/p52, LIGHT also activates Stat3. Activation of Stat3 together with activating non-canonical
NF-kappaB/p52 signaling by LIGHT may maximize its effects on cellular proliferation, survival, and
inflammation.