Abstract
Scoparone, a natural compound isolated from Artemisia capillaris, has been used in Chinese herbal medicine to treat neonatal jaundice. Signal transducer and activator of transcription 3 (STAT3) contributes to the growth and survival of many human tumors. This study was undertaken to investigate the anti-tumor activity of scoparone against DU145 prostate cancer cells and to determine whether its effects are mediated by inhibition of STAT3 activity. Scoparone inhibited proliferation of DU145 cells via cell cycle arrest in G1 phase. Transient transfection assays showed that scoparone repressed both constitutive and IL-6-induced transcriptional activity of STAT3. Western blot and quantitative real-time PCR analyses demonstrated that scoparone suppressed the transcription of STAT3 target genes such as cyclin D1, c-Myc, survivin, Bcl-2, and Socs3. Consistent with this, scoparone decreased phosphorylation and nuclear accumulation of STAT3, but did not reduce phosphorylation of janus kinase 2 (JAK2) or Src, the major upstream kinases responsible for STAT3 activation. Moreover, transcriptional activity of a constitutively active mutant of STAT3 (STAT3C) was inhibited by scoparone, but not by AG490, a JAK2 inhibitor. Furthermore, scoparone treatment suppressed anchorage-independent growth in soft agar and tumor growth of DU145 xenografts in nude mice, concomitant with a reduction in STAT3 phosphorylation. Computational modeling suggested that scoparone might bind the SH2 domain of STAT3. Our findings suggest that scoparone elicits an anti-tumor effect against DU145 prostate cancer cells in part through inhibition of STAT3 activity.
Highlights
Prostate cancer is the second most common cancer and the sixth leading cause of cancer death in men worldwide [1]
To further determine whether the anti-proliferative effect of scoparone is due to inhibition of cell-cycle progression or induction of apoptosis, we carried out a flow cytometric analysis of the cell cycle in DU14 cells, which were the most sensitive to the growth-inhibitory effect of scoparone
We demonstrated the anti-tumor effects of scoparone on DU145 prostate cancer cells both in vitro and in vivo, and partially delineated the underlying molecular mechanism
Summary
Prostate cancer is the second most common cancer and the sixth leading cause of cancer death in men worldwide [1]. Even with docetaxel-based chemotherapy, treatment of patients with metastatic CRPC remains a major clinical challenge In this context, the signal transducer and activator of transcription 3 (STAT3) signaling pathway has been validated as a promising therapeutic target in metastatic prostate cancer: this protein is aberrantly activated in prostate cancer and contributes to the promotion of metastatic progression [4,5]. Its phosphorylation is transient and tightly regulated in normal non-transformed cells, STAT3 is persistently activated in a variety of human tumors, including hematological malignancies (leukemia, multiple myeloma and lymphoma) and solid tumors (head and neck squamous cell carcinoma [HNSCC], melanoma, colon, hepatoma, breast, and prostate cancers) [13,14,15,16,17]. STAT3 is considered to represent a promising molecular target for development of anti-cancer therapeutics using both direct and indirect approaches [13,14,21]
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