nsc-74859 and Prostatic-Neoplasms

Bone metastatic prostate cancer (PCa) promotes mesenchymal stem cell (MSC) recruitment and their differentiation into osteoblasts. However, the effects of bone-marrow derived MSCs on PCa cells are less explored. Here, we report MSC-derived interleukin-28 (IL-28) triggers prostate cancer cell apoptosis via IL-28 receptor alpha (IL-28Rα)-STAT1 signaling. However, chronic exposure to MSCs drives the selection of prostate cancer cells that are resistant to IL-28-induced apoptosis and therapeutics such as docetaxel. Further, MSC-selected/IL-28-resistant prostate cancer cells grow at accelerated rates in bone. Acquired resistance to apoptosis is PCa cell intrinsic, and is associated with a shift in IL-28Rα signaling via STAT1 to STAT3. Notably, STAT3 ablation or inhibition impairs MSC-selected prostate cancer cell growth and survival. Thus, bone marrow MSCs drive the emergence of therapy-resistant bone metastatic prostate cancer yet this can be disabled by targeting STAT3.

Topics: Adenocarcinoma; Aminosalicylic Acids; Animals; Apoptosis; Benzenesulfonates; Bone Neoplasms; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Culture Media, Conditioned; Disease Models, Animal; Docetaxel; Humans; Interferons; Male; Mesenchymal Stem Cells; Mice, Knockout; Osteoblasts; Primary Cell Culture; Prostatic Neoplasms; Receptors, Interferon; Recombinant Proteins; RNA, Small Interfering; STAT1 Transcription Factor; STAT3 Transcription Factor; Tibia

WASF3 has been shown to be required for invasion and metastasis in different cancer cell types and knockdown of WASF3 leads to suppression of invasion/metastasis. Aberrant signaling through the interleukin 6/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) axis in cancer cells has emerged as a major mechanism for cancer progression. In this study, we demonstrate that interleukin 6 induces both WASF3 expression and phosphoactivation in breast and prostate cancer cell lines through the JAK2/STAT3 pathway in two different ways. First, we show that STAT3 binds directly to the WASF3 promoter and increases transcription levels, which correlates with increased migration potential. Inactivation of STAT3 with short hairpin RNA, dominant negative constructs or S3I-201 leads to reduced WASF3 levels and reduced migration. Second, we have shown that JAK2, while activating STAT3, also interacts with and activates WASF3. Inhibition of JAK2 with short hairpin RNA or AG490 leads to loss of migration due to reduced WASF3 activation levels and prevention of its membrane localization. Together, these results define a novel signaling network whereby JAK2/STAT3 signaling creates a feed-forward loop to raise activated WASF3 levels that promote cancer cell motility.

Topics: Aminosalicylic Acids; Benzenesulfonates; Cell Movement; Gene Expression Regulation, Neoplastic; Humans; Interleukin-6; Janus Kinase 2; Male; Promoter Regions, Genetic; Prostatic Neoplasms; Protein Binding; Signal Transduction; STAT3 Transcription Factor; Wiskott-Aldrich Syndrome Protein Family