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Natural Product Trienomycin A is a STAT3 pathway inhibitor that exhibits potent in vitro and in vivo efficacy against pancreatic cancer
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  • Qiu-Rui He,
  • Jiang-Jiang Tang,
  • Zhi-Fan Chen,
  • Yao Liu,
  • Huang Chen,
  • Ding Li,
  • Zhengfang Yi,
  • Jin-Ming Gao
Qiu-Rui He
Northwest A&F University
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Jiang-Jiang Tang
Northwest A&F University
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Zhi-Fan Chen
Northwest A&F University
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Yao Liu
Northwest A&F University
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Huang Chen
East China Normal University School of Life Sciences
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Ding Li
Northwest A&F University
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Zhengfang Yi
East China Normal University School of Life Sciences
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Jin-Ming Gao
Northwest A&F University
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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.

Peer review status:ACCEPTED

19 Oct 2020Submitted to British Journal of Pharmacology
20 Oct 2020Submission Checks Completed
20 Oct 2020Assigned to Editor
03 Nov 2020Reviewer(s) Assigned
27 Dec 2020Review(s) Completed, Editorial Evaluation Pending
29 Dec 2020Editorial Decision: Revise Minor
24 Jan 20211st Revision Received
24 Jan 2021Assigned to Editor
24 Jan 2021Submission Checks Completed
25 Jan 2021Reviewer(s) Assigned
26 Jan 2021Review(s) Completed, Editorial Evaluation Pending
03 Feb 2021Editorial Decision: Revise Minor
10 Feb 20212nd Revision Received
11 Feb 2021Assigned to Editor
11 Feb 2021Submission Checks Completed
11 Feb 2021Review(s) Completed, Editorial Evaluation Pending
15 Feb 2021Editorial Decision: Accept