nsc-74859 and Bone-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

Osteosarcoma is often a fatal malignancy. Constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis. We aimed to investigate the effect and potential molecular mechanisms of STAT3 inhibition on osteosarcoma.. STAT3 inhibitor S3I-201 was investigated in six osteosarcoma cell lines. Crystal violet colorimetric, clonogenic, cleaved caspase-3 assays and western blot were performed to measure the effect and mechanisms of STAT3 inhibition.. All osteosarcoma cell lines expressed phosphorylated STAT3. Anti-proliferative effects of S3I-201 were dose- and time-dependent. S3I-201 also inhibited colony-formation and induced apoptosis through the caspase cleavage pathway. Finally, molecular mechanism studies suggested that down-regulation of STAT3 phosphorylation and downstream STAT3-target genes such as cyclin D1 and survivin may contribute to S3I-201-mediated anti-proliferation and apoptosis.. Inhibition of STAT3 signalling suppressed osteosarcoma cell growth and induced apoptosis, and indicated that STAT3 targeted-therapy may have therapeutic potential in osteosarcoma.

Topics: Aminosalicylic Acids; Apoptosis; Benzenesulfonates; Blotting, Western; Bone Neoplasms; Cell Proliferation; Humans; Osteosarcoma; STAT3 Transcription Factor; Tumor Cells, Cultured; Tumor Stem Cell Assay