STAT3 inhibition of cholangiocarcinoma cell lines reduces viability and restricts the release of immunosuppressive cytokines in vitro.

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Date

2015-05

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The Ohio State University

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Abstract

Cholangiocarcinoma (CC) is the malignant transformation of epithelial cells originating from the bile ducts. This cancer has an abysmal 3 year survival rate of only 10% and is typically unresponsive to standard surgical and chemotherapeutic practices7. Therefore, novel treatment strategies are desperately needed against this malignancy. One important feature of CC cells is their autocrine secretion of interleukin-6 (IL-6)6,9,10. The secretion of IL-6 can activate numerous pro-oncogenic signaling pathways including STAT3 within the tumor cell, while simultaneously promoting immunologic changes in patients with advanced disease. We hypothesized that inhibition of Signal-Transducer and Activator of Transcription-3 (STAT3) pathway may elicit a dual effect by promoting apoptosis of human BC cell lines, and limiting the secretion of immunosuppressive cytokines from these cells. A panel of human CC cell lines (n=7) with various genotypic profiles demonstrated secretion of IL-6 (range 0-6593 pg/mL). Six of the seven lines assessed had constitutively phosphorylated STAT3 as determined by western blot. A novel small molecule inhibitor, FLLL100, can directly inhibit Tyr705 phosphorylation within the SH2 domain of STAT3, and induced apoptosis in the CC cell lines regardless of genotypic profile. These effects were observed within 24 hours of drug exposure at micromolar concentrations. Immunoblot analysis of PARP cleavage confirmed apoptosis. Exposure of CC cell lines to FLLL100 resulted in decreased secretion of IL-6 in culture supernatants. Together, these data indicate that the IL-6/STAT3 signaling axis plays a role in human CC survival and that targeting this pathway can limit immune suppressive factors derived from CC cell lines.

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cancer, STAT3, small molecule inhibition, cholangiocarcinoma

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