Natural Product Trienomycin A is a STAT3 pathway inhibitor that exhibits
potent in vitro and in vivo efficacy against pancreatic cancer
Abstract
Background and Purpose: Pancreatic cancer is an exceptionally fatal
disease. However, therapeutic drugs for pancreatic cancer have presented
a serious shortage over the past few decades. Signal Transducer and
Activator of Transcription-3 (STAT3) is persistently activated in many
human cancers where it promotes tumor development and progression.
Natural products serve as an inexhaustible source of anticancer drugs.
Here, we identified the natural product Trienomycin A (TA), an ansamycin
antibiotic, as a potential inhibitor of the STAT3 pathway with potent
activity against pancreatic cancer. Experimental Approach: Utilizing the
STAT3-luciferase (STAT3-luc) reporter system, we found that TA potently
inhibits the transcriptional activity of STAT3. We subsequently
investigated in vitro and in vivo inhibitory activity of TA against
pancreatic cancer and its potential mechanism by using the molecular
docking, SPR assay, MTS assay, colony formation assay, transwell
migration/invasion assay, flow cytometric analysis, immunofluorescence
staining, quantitative real-time PCR, western blotting, tumor xenograft
model, H&E staining and immunohistochemistry. Key Results: TA directly
bound to STAT3 and inhibited STAT3 (Tyr705) phosphorylation, leading to
the inhibition of the STAT3 pathway. TA significantly inhibited the
colony formation, proliferation, migration and invasion of pancreatic
cancer cell lines. TA dramatically blocked pancreatic tumor growth. More
importantly, TA did not show obvious toxicity at the effective dose in
mice. Conclusions and Implications: TA exhibits antineoplastic activity
by suppressing the STAT3 activation in pancreatic cancer. TA could be a
novel therapeutic candidate for pancreatic cancer by blocking the STAT3
pathway.