3,3′-Diindolylmethane suppresses ovarian cancer cell viability and metastasis and enhances chemotherapy sensitivity via STAT3 and Akt signaling in vitro and in vivo

Abstract Signal transducer and activator of transcription-3 (STAT3) protein is constitutively activated in ovarian cancer. The purpose of this study was to investigate the effects of 3,3′-diindolylmethane (DIM) on the regulation of STAT3 signaling and ovarian cancer cell viability, invasion, and sensitivity to chemotherapy. Ovarian cancer SKOV3 and A2780 cell lines were treated with various concentrations of DIM for different periods of time for assessment of cell viability as well as gene expression before and after knockdown of STAT3 expression using STAT3 shRNA. DIM treatment potently suppressed the viabilities of ovarian cancer cells. Consequently, DIM inhibited xenograft growth in nude mice. In addition, at the gene level, DIM inhibited phosphorylation of STAT3 and AKT proteins and expression of their downstream proteins. Moreover, knockdown of STAT3 expression significantly enhanced DIM antitumor activity and cisplatin sensitivity. Their combination suppressed the protein expression of survivin, Bcl-2, Mcl-1, HIF-1α, VEGF, and MMPs, but activated caspase-3. Taken together, the antitumor activity of DIM is via inhibition of the STAT3 and Akt signaling pathways. The combination of STAT3 knockdown with DIM treatment could be further evaluated as a therapeutic strategy for the treatment of advanced ovarian cancer.