ORCID
Qiu-Rui He https://orcid.org/0000-0001-6823-3845
Jin-Ming Gao https://orcid.org/0000-0003-4801-6514
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.
Keywords: Trienomycin A; STAT3; Pancreatic cancer; Ansamycins;
Natural product