ABSTRACT
Cytokeratin 20 (CK20) is an intermediate filament that is known to be a prognostic marker in several types of cancer. However, little is known about CK20 expression and tumor metastasis in tamoxifen-resistant MCF-7 (TRM-7) breast cancer cells. TRM-7 cells overexpress CK20, resulting in enhanced invasiveness in vitro. CK20 silencing reduced the invasiveness of TRM-7 cells. Moreover, CK20 expression in MCF-7 cells was regulated by peroxisome proliferator-activated receptor γ (PPARγ). Our findings suggest that PPARγ-dependent CK20 expression enhances the metastatic potential of MCF-7 breast cancer cells and may be a potential therapeutic target in tamoxifen-resistant breast cancer.
Subject(s)
Antineoplastic Agents, Hormonal/pharmacology , Keratin-20/metabolism , Neoplasm Invasiveness , Tamoxifen/pharmacology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Drug Resistance, Neoplasm , Humans , Keratin-20/genetics , PPAR gamma/genetics , PPAR gamma/metabolismABSTRACT
Persistently activated JAK/STAT3 signaling pathway plays a pivotal role in various human cancers including major carcinomas and hematologic tumors, and is implicated in cancer cell survival and proliferation. Therefore, inhibition of JAK/STAT3 signaling may be a clinical application in cancer therapy. Here, we report that 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo [1,3]oxathiol-4-one (BOT-4-one), a small molecule inhibitor of JAK/STAT3 signaling, induces apoptosis through inhibition of STAT3 activation. BOT-4-one suppressed cytokine (upd)-induced tyrosine phosphorylation and transcriptional activity of STAT92E, the sole Drosophila STAT homolog. Consequently, BOT-4-one significantly inhibited STAT3 tyrosine phosphorylation and expression of STAT3 downstream target gene SOCS3 in various human cancer cell lines, and its effect was more potent in JAK3-activated Hodgkin's lymphoma cell line than in JAK2-activated breast cancer and prostate cancer cell lines. In addition, BOT-4-one-treated Hodgkin's lymphoma cells showed decreased cell survival and proliferation by inducing apoptosis through down-regulation of STAT3 downstream target anti-apoptotic gene expression. These results suggest that BOT-4-one is a novel small molecule inhibitor of JAK3/STAT3 signaling and may have therapeutic potential in the treatment of human cancers harboring aberrant JAK3/STAT3 signaling, specifically Hodgkin's lymphoma.
