The role of constitutively activated STAT3 in B16 melanoma cells.

Constitutively activated STAT3 is found frequently in a wide variety of human tumors, including melanoma. Moreover, constitutive STAT3 activation actively participates in tumor formation and progression, making STAT3 an attractive target for cancer therapy. We report here that in murine B16 melanoma cells, which have been previously shown to express constitutively active STAT3, the expression of a mutant form of STAT3 with the canonical tyrosine phosphorylation site (residue 705) mutated to phenylanaine has dominant-negative properties (STAT3-DN). STAT3-DN inhibits STAT3 tyrosine phosphorylation and STAT3-dependent DNA binding activity. Most importantly, STAT3-DN expression in B16 cells inhibits their invasiveness, as well as their melanogenesis by down-regulation of tyrosinase mRNA and protein expression as well as tyrosinase activity. These results suggest that STAT3 signaling plays a critical role in regulating melanoma behavior, and may represent a druggable target for melanoma therapy.