A Specific STAT3-Binding Peptide Exerts Antiproliferative Effects and Antitumor Activity by Inhibiting STAT3 Phosphorylation and Signaling

Abstract

STAT3 promotes the survival, proliferation, metastasis, immune escape, and drug resistance of cancer cells, making its targeting an appealing prospect. However, although multiple inhibitors of STAT3 and its regulatory or effector pathway elements have been developed, bioactive agents have been somewhat elusive. In this report, we report the identification of a specific STAT3-binding peptide (APT(STAT3)) through phage display of a novel "aptide" library. APT(STAT3) bound STAT3 with high specificity and affinity (similar to 231 nmol/L). Addition of a cell-penetrating motif to the peptide to yield APT(STAT3)-9R enabled uptake by murine B16F1 melanoma cells. Treatment of various types of cancer cells with APT(STAT3)-9R blocked STAT3 phosphorylation and reduced expression of STAT targets, including cyclin D1, Bcl-xL, and survivin. As a result, APT(STAT3)-9R suppressed the viability and proliferation of cancer cells. Furthermore, intratumoral injection of APT(STAT3)-9R exerted potent antitumor activity in both xenograft and allograft tumor models. Our results offer a preclinical proof-of-concept for APT(STAT3) as a tractable agent for translation to target the broad array of cancers harboring constitutively activated STAT3.