A novel oncogenic function of STAT3 and the molecular mechanism underlying its inactivation by curcumin

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is latent but aberrantly activated in the majority of cancers. STAT3 has been shown to play a key role in inflammation-associated tumorigenesis. Thus, this transcription is an attractive molecular target for the development of new cancer therapeutics. A large number of therapeutic strategies have explored selective inhibition of STAT3 signaling, such as small molecule inhibitors, natural compounds and interference oligonucleotides. Curcumin is a natural compound isolated from the turmeric (Curcuma longa L., Zingiberaceae) that has been reported to have inhibitory effects on STAT3 signaling. However, the mechanisms underlying the inactivation of this transcription factor are still elusive. In this study, I found that curcumin inhibits persistently overactivated STAT3 signaling in H-Ras transformed breast epithelial cells (H-Ras MCF10A). STAT3 has been found to be sensitive to redox regulation. Therefore, thiol modifications of specific cysteine residues in this transcription factor largely affect its conformation and transcriptional activity. I found the cysteine residue 259 of STAT3 as a putative binding site of curcumin through a computer docking and LC-MS/MS analyses. Moreover, curcumin failed to interact with cysteine 259-mutated STAT3 and to induce apoptosis. The electrophilic α,β-unsaturated carbonyl moiety of curcumin appears to be essesntial for its binding to STAT3 in H-Ras MCF10A cells. Tetrahydrocurcumin that lacks such moiety barely inhibited STAT3 and induced apoptosis in the same cell line. Taken together, these findings suggest that curcumin can abrogate aberrant activation of STAT3 through direct interaction, thereby inhibiting STAT3-mediated mammary carcinogenesis. <br/> Besides STAT3, nuclear factor-κB (NF-κB) plays pivotal roles in inflammation and inflammation-associated tumorigenic processes. Emerging evidence has shown that these two transcription factors cooperatively promote cancer development through regulation of a subset of genes. STAT3 and NF-κB control both distinct and overlapping genes in tumorigenesis. NF-κB activation is commonly regulated by IκB kinases (IKKs). However, interactions between STAT3 and IKK still remain largely unknown. In the present study, I found that STAT3 regulates the expression of IKKα without affecting that of the other subunits, IKKβ and γ in H-Ras MCF10A cells. I also observed that STAT3 binds to and stabilizes IKKα protein, thereby regulating the p100/p52 processing in the noncanonical NF-κB pathway. Based on these findings, it is speculated that STAT3 mediated-IKKα stabilization can contribute to mammary carcinogensis. Notably, curcumin downregulated the IKKα expression but not its mRNA expression. Moreover, tetrahydrocurcumin that lacks the α,β-unsaturated carbonyl moiety failed to decrease the protein level of this kinase and to inhibit cell growth. Thus, it is likely that curcumin downregulates IKKα expression probably through direct interaction with STAT3. <br/> <br/>